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Enhancing NAD+ Efficiency by Energizing Sirtuins

<p style="text-align: justify;">Researchers publishing in <i>Physical Review X</i> have discovered <a href="https://journals.aps.org/prx/abstract/10.1103/PhysRevX.14.041019">compounds that can double the efficiency of the sirtuin SIRT3 in processing NAD+</a>.</p> <h2 style="text-align: justify;"><b>Looking for a new way to boost enzymes</b></h2> <p style="text-align: justify;">The researchers begin their paper by noting that most drugs administered to people are geared towards inhibition of particular enzymes in order to treat a disease. In this case, however, the goal is the opposite: to boost the function of an enzyme, thereby boosting a healthy phenotype rather than battling back a diseased one.</p> <p style="text-align: justify;"><div class="wpv-grid grid-1-1 wpv-first-level unextended animation-from-left"><div class="topic-box-item" style="background-color:#fff"><a href="https://www.lifespan.io/topic/nad-nicotinamide-adenine-dinucleotide-benefits-side-effects/" class="topic-thumb-link"><div class="topic-box-thumb-wrap topic-thumb-align-left"><div class="topic-box-thumb" style="background:url(https://www.lifespan.io/wp-content/uploads/2019/08/NADH.jpg) no-repeat center center;background-size: contain;"><img fetchpriority="high" decoding="async" width="800" height="450" src="https://www.lifespan.io/wp-content/uploads/2019/08/NADH.jpg" class="attachment-full size-full wp-post-image" alt="Diagram of NADH" srcset="https://www.lifespan.io/wp-content/uploads/2019/08/NADH.jpg 800w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-400x225.jpg 400w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-704x396.jpg 704w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-256x144.jpg 256w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-300x169.jpg 300w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-150x84.jpg 150w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-480x270.jpg 480w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-600x338.jpg 600w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-360x203.jpg 360w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-262x147.jpg 262w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-555x312.jpg 555w, https://www.lifespan.io/wp-content/uploads/2019/08/NADH-768x432.jpg 768w" sizes="(max-width: 800px) 100vw, 800px" /></div></div></a><a class="topic-info-link" href="https://www.lifespan.io/topic/nad-nicotinamide-adenine-dinucleotide-benefits-side-effects/"><div class="topic-box-title">Nicotinamide Adenine Dinucleotide (NAD): Benefits and Research</div><div class="topic-box-desc">Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.<br><span class="topi-read-more">Read More</span></div></a></div></div><style>.institute-box-title,.page-contribution-history #main-content .entry-content,.page-manage-saved-cards #main-content .entry-content,.page-manage-subscriptions #content,.reference-box-title,.topic-box-title{padding-top:10px}.blog-page-wrapper #sidebar #an-mailchimp-email-2:after,.facebook-feed-wrapper:after,.grid-1-2 .topic-box-item:after,.leaf-grid-row:after,.post-actions-wrapper:after,.reference-box-item:after,.topic-box-item:after{content:'';display:table;clear:both}.grid-1-1,.grid-1-2,.grid-1-3,.grid-1-4,.grid-1-5,.grid-1-6,.grid-2-3,.grid-2-5,.grid-3-4,.grid-3-5,.grid-4-5,.grid-5-6{padding:0 15px;float:left;box-sizing:border-box}.wpv-grid img{max-width:100%;display:block;height:auto}.wpv-grid.grid-1-1{width:100%;clear:both}.institute-box-item,.reference-box-item,.topic-box-item{max-width:300px;margin-bottom:30px}.institute-box-thumb-wrap .institute-box-thumb,.reference-box-thumb-wrap .reference-box-thumb,.topic-box-thumb-wrap .topic-box-thumb{display:block;border:15px solid #fff;width:100%;height:150px;box-sizing:border-box}.topic-box-thumb-wrap{border:1px solid #ddd}.institute-box-thumb-wrap .institute-box-thumb img,.reference-box-thumb-wrap .reference-box-thumb img,.topic-box-thumb-wrap .topic-box-thumb img{opacity:0;max-width:100%;height:auto;visibility:hidden}.reference-box-item,.topic-box-item{max-width:100%;border:1px solid #ddd;padding:15px}.reference-box-thumb-wrap,.topic-box-thumb-wrap{max-width:300px;border:none}.reference-box-thumb-wrap .reference-box-thumb,.topic-box-thumb-wrap .topic-box-thumb{height:inherit;padding:0;border:none;margin:30px 0 15px;height:inherit}.reference-box-title,.reference-box-title a,.topic-box-title,.topic-box-title a{font-weight:700;text-transform:uppercase;font-size:20px;color:#4d4d4d!important;margin-bottom:5px;display:block}.reference-box-item a.reference-info-link,.topic-box-item a.topic-info-link{display:block;color:#565656;text-decoration:none}.reference-box-desc,.topic-box-desc{margin-bottom:10px;padding-bottom:10px;border-bottom:1px solid #ddd}.reference-box-thumb-wrap.reference-thumb-align-left,.topic-box-thumb-wrap.topic-thumb-align-left{float:left;margin-right:30px;width:40%;margin-bottom:10px}.topic-box-desc{border-bottom:none;text-align:justify}@media (max-width:958px){.leaf-template .grid-1-2:last-child,.leaf-template .grid-1-3:last-child,.leaf-template .grid-1-4:last-child,.leaf-template .grid-1-5:last-child,.leaf-template .grid-1-6:last-child,.leaf-template .grid-2-3:last-child,.leaf-template .grid-2-5:last-child,.leaf-template .grid-3-4:last-child,.leaf-template .grid-3-5:last-child,.leaf-template .grid-4-5:last-child,.leaf-template .grid-5-6:last-child,.leaf-template .site .grid-1-1,.leaf-template .site .grid-1-1:last-child{margin-bottom:0}}@media all and (max-width:767px){.reference-box-thumb-wrap.reference-thumb-align-left,.reference-box-thumb-wrap.reference-thumb-align-right,.topic-box-thumb-wrap.topic-thumb-align-left,.topic-box-thumb-wrap.topic-thumb-align-right{width:100%;float:none;margin:0}}</style></p> <p style="text-align: justify;">Sirtuins are enzymes that have been heavily investigated in the context of aging. They rely on NAD+ to function, and these researchers describe them as being critical regulators of cellular pathways relating to aging [1]. Upregulating sirtuins has been found in considerable previous work to extend lifespan in mammals [2]. However, most methods of using drugs to boost sirtuins has relied on allosteric activation, a chemical process that relies on an existing substrate that might be limited in quantity [3].</p> <p style="text-align: justify;">Of course, as sirtuins rely on NAD+, there has been much work on directly influencing that instead. These researchers note two problems with that approach: as it is a common aspect of metabolism, boosting NAD+ across the board may result in broad side effects [4] and converting it into NADH relies on delivering it into cells that have functioning internal machinery [5], which, in the context of aging, is far from guaranteed.</p> <p style="text-align: justify;">Therefore, these researchers seek to allow sirtuins to do more with less: to continue to function adequately even when NAD+ is diminished. This, the researchers describe, is a trickier thing to do; while allosteric activators fundamentally rely on existing, evolved mechanisms, attempting to modulate these enzymes is similar to designing new enzymes outright.</p> <p style="text-align: justify;">Also, they needed a compound that works all the time: a steady-state activator. Previous work has created compounds that inhibit, rather than activate, sirtuins most of the time [6], only performing their desired function under specific conditions.</p> <p style="text-align: justify;">SIRT3 was chosen as the target for two reasons. The first is that it is known to have beneficial effects on mitochondria [7], and previous work has found that the benefits of NAD+ against mitochondrial dysfunction are due to SIRT3 [8]. The second is that natural mutations in the SIRT3 gene are connected to longevity [9].</p> <h2 style="text-align: justify;"><b>Needle in a haystack</b></h2> <p style="text-align: justify;">Using an advanced algorithm, the researchers searched a library of 1.2 million compounds by beginning with Honokiol, a compound that only activates SIRT3 under certain conditions. The researchers were able to find compounds that do steady state and non-steady state activation, with which they refined their experiments further with a close and detailed examination of the specific biochemistry involved, looking for compounds that have strong bonds to certain amino acids on the SIRT3 protein.</p> <p style="text-align: justify;">This initial work, however, was all done on computers. To verify their findings in the real world, the authors administered their compounds to real SIRT3 in a substrate. While a lot of this type of work uses fluorescent labeling, the authors eschewed that approach as it may have affected the results. One particularly strong compound, number 5689785, was identified as being a plausible drug after this screening process.</p> <p style="text-align: justify;">The researchers tested their new candidate against a control group, honokiol, and the well-known NAD+ precursor NMN. In nearly all cases, 5689785 performed favorably against these alternatives. Administering nicotinamide (NAM) to cells inhibits NAD+ enzymatic activity, but 5689785 was able to restore it in a way that honokiol could not.</p> <h2 style="text-align: justify;"><b>Next steps</b></h2> <p style="text-align: justify;">This is not a drug yet; it has not been formulated in a way that is consumable by living organisms, and so there were no animal studies done. What the researchers have is an initial compound with which to continue the process of drug development. Their goal was to prove that it is indeed possible to directly enhance the activity of sirtuins without relying on substrate-based methods. If this approach sees success in animal models, it could pave the way for drugs that, due to SIRT3&#8217;s mitochondrial effects, fight multiple aspects of aging.</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--f9c19200118a810 a {background-color:#1e4fba;}.rb--f9c19200118a810 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--f9c19200118a810"><a href="https://www.lifespan.io/how-you-can-help/" target="_self">Yes I will donate❤️</a></div></div></div> </div> <h2 style="text-align: justify;"><b>Literature</b></h2> <p style="text-align: justify;">[1] Kaeberlein, M., McVey, M., &amp; Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. <i>Genes &amp; development</i>, <i>13</i>(19), 2570-2580.</p> <p style="text-align: justify;">[2] Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., &#8230; &amp; Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. <i>Nature communications</i>, <i>12</i>(1), 3208.</p> <p style="text-align: justify;">[3] Sinclair, D. A., &amp; Guarente, L. (2014). Small-molecule allosteric activators of sirtuins. <i>Annual review of pharmacology and toxicology</i>, <i>54</i>(1), 363-380.</p> <p style="text-align: justify;">[4] Yang, T., &amp; Sauve, A. A. (2006). NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity. <i>The AAPS journal</i>, <i>8</i>, E632-E643.</p> <p style="text-align: justify;">[5] Hu, Q., Wu, D., Walker, M., Wang, P., Tian, R., &amp; Wang, W. (2021). Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments. <i>Cell reports methods</i>, <i>1</i>(7).</p> <p style="text-align: justify;">[6] Reverdy, C., Gitton, G., Guan, X., Adhya, I., Dumpati, R. K., Roy, S., &#8230; &amp; Chakrabarti, R. (2022). Discovery of novel compounds as potent activators of Sirt3. <i>Bioorganic &amp; medicinal chemistry</i>, <i>73</i>, 116999.</p> <p style="text-align: justify;">[7] Van de Ven, R. A., Santos, D., &amp; Haigis, M. C. (2017). Mitochondrial sirtuins and molecular mechanisms of aging. <i>Trends in molecular medicine</i>, <i>23</i>(4), 320-331.</p> <p style="text-align: justify;">[8] Cantó, C., Houtkooper, R. H., Pirinen, E., Youn, D. Y., Oosterveer, M. H., Cen, Y., &#8230; &amp; Auwerx, J. (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell metabolism, 15(6), 838-847.</p> <p style="text-align: justify;">[9] Bellizzi, D., Rose, G., Cavalcante, P., Covello, G., Dato, S., De Rango, F., &#8230; &amp; De Benedictis, G. (2005). A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. <i>Genomics</i>, <i>85</i>(2), 258-263.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134830&quot; data-voice=&quot;en-US-BrandonNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134830&amp;voice=en-US-BrandonNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

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The Impact of a Human Breast Milk Probiotic on Sarcopenia

<p style="text-align: justify;">A recent study linked probiotic-induced gut microbiome and metabolite changes to <a href="https://pubmed.ncbi.nlm.nih.gov/39632843/">improved muscle functioning in older sarcopenia patients</a> [1].</p> <h2 style="text-align: justify;"><b>Sarcopenia and the gut</b></h2> <p style="text-align: justify;">Sarcopenia is an age-related condition. People with sarcopenia suffer from a reduction in muscle mass, strength, and function, leading to a decreased quality of life and increased morbidity and mortality [2].</p> <p style="text-align: justify;">The authors of this study, citing evidence of a link between the gut microbiome, muscle health, and sarcopenia, investigated the effect of the consumption of a probiotic on the muscle health of sarcopenia patients. They used <i>Bifidobacterium animalis subsp. Lactis Probio-M8 </i>(Probio-M8), a probiotic strain present in human breast milk [3]. Probio-M8 has already been shown to have a positive impact on bone metabolism [4] and in the treatment of Parkinson’s disease in older adults [5].</p> <h2 style="text-align: justify;"><b>Anti-aging effects in mice</b></h2> <p style="text-align: justify;">The researchers administered Probio-M8 to 19-month-old mice for 28 days. They observed improved muscle function and a significant reduction in senescence in the mice that received probiotics, suggesting an anti-aging effect.</p> <p style="text-align: justify;">The researchers also investigated inflammatory markers but didn’t see significant differences between the treatment and control groups. They suggest that this might be due to existing low inflammation in the control group, which does not allow probiotic treatment to lower it further.</p> <h2 style="text-align: justify;"><b>Impact on microbes and metabolites</b></h2> <p style="text-align: justify;">The impact of probiotic treatment on the structure and diversity of the gut microbiome in old mice was limited. A deeper look into the 10 most populous bacterial species in these groups&#8217; fecal matter revealed a pathogen (<i>Mucispirillum schaedleri</i>) that was far more abundant in the control group. Previous reports suggested that this microbe may cause ulcerative colitis [6]. This is in contrast to probiotic-treated mice, in which the researchers observed abundant beneficial microbes.</p> <p style="text-align: justify;">There were also beneficial changes in the metabolites in the fecal and serum samples of old mice treated with the probiotic. The treatment led to a significant increase in anti-inflammatory, anticancer, and antioxidant metabolites, metabolites that have been reported to have benefits against aging, and metabolites that may somewhat alleviate neurological disorders, such as Alzheimer’s disease and Parkinson’s disease.</p> <h2 style="text-align: justify;"><b>The chair test</b></h2> <p style="text-align: justify;">The promising results in mice led to a test of this probiotic on 43 older sarcopenia patients. Following 60 days of supplementation with Probio-M8, the researchers observed a roughly 16% reduction in the five-time chair stand (FTCS) test time among the treated patients. This test requires patients to sit and stand up five times and measures lower limb strength. This significant result suggests an improvement in overall physical performance.</p> <p style="text-align: justify;">However, other sarcopenia-related measurements didn’t support the optimistic results obtained in the FTCS test. Skeletal muscle mass, grip strength, calf circumference, and BMI didn’t significantly change following the probiotic treatment.</p> <p style="text-align: justify;">Additionally, an evaluation of multiple physiological sarcopenia-related measurements showed mostly no changes compared to controls, except for reduced total cholesterol.</p> <h2 style="text-align: justify;"><b>The role of microbial metabolites</b></h2> <p style="text-align: justify;">Similarly to the results obtained in mice, human samples also showed modest changes in the richness and structure of the gut microbiome after probiotic treatment. Some of the most significant changes included increased numbers of beneficial gut bacteria, and reduced numbers of pathogenic gut bacteria, in patients with sarcopenia.</p> <p style="text-align: justify;">Despite modest changes in microbial composition, the researchers observed significant metabolite changes: the probiotic treatment enriched the microbial pathways involved in vitamin C biosynthesis and nucleotide metabolism. The researchers suggest that higher activity of those pathways might play a role in microbes&#8217; support for host antioxidant defenses and nucleotide availability.</p> <p style="text-align: justify;">Other metabolites that were increased in feces and serum are involved in anti-inflammatory effects and processes essential for vital physiological functions, or they are associated with skeletal muscle, such as metabolites promoting the proliferation of skeletal muscle cells. There was also an increase in a compound that is considered a source of muscle energy and important for promoting muscle protein synthesis: creatine.</p> <p style="text-align: justify;">The researchers noted that the impact of the probiotic treatment on the composition of the gut microbiome was modest. However, the impact on the metabolite changes was significant, leading them to further investigations into how probiotic-driven metabolite changes influence host physical performance.</p> <p style="text-align: justify;">A series of bioinformatic analyses and models were employed to identify key players in the connection between Probio-M8 and sarcopenia. The authors summarized that their analysis “suggests that Probio-M8 may positively influence muscle metabolism, potentially through its effects on the gut microbiome and subsequent modulation of creatine synthesis or utilization.”</p> <p style="text-align: justify;">A computational analysis of metabolites also pointed the researchers toward a hypothesis that one of the harmful molecules known as n-dodecyl-l-homoserine lactone (HSL) “could reduce the absorption of creatine from the gut.” To test this, they created a cell culture monolayer of enterocytes. Enterocytes are intestinal absorptive cells that are located on the inner surface of the small and large intestines. An experiment confirmed that HSL interfered with creatine transport by affecting the level of its transporter (CRT).</p> <h2 style="text-align: justify;"><b>Molecular understanding</b></h2> <p style="text-align: justify;">In the discussion section, the researchers gathered the molecular evidence that they and others presented to assemble a possible mechanism of action.</p> <p style="text-align: justify;">One of the key players appears to be creatine, and these researchers have found that this probiotic encourages creatine to be delivered into the bloodstream from the gut. Creatine is a compound essential for muscles and, when combined with resistance training, can increase lean mass and muscle strength in older adults. Previous research suggested that creatine supplementation has benefits in older adults with sarcopenia [7]. The authors suggest that creatine might “act as a buffer to inhibit the production of reactive oxygen species (ROS) by serving as a neutralizing agent.” The inhibition of ROS is important, since accumulation of ROS has been linked to muscle function and muscle loss [8].</p> <blockquote> <p style="text-align: justify;">Probio-M8 can inhibit the enrichment of HSL in patients with sarcopenia, thereby promoting the accumulation of creatine in the serum and improving the host’s overall physical performance.</p> </blockquote> <p><img fetchpriority="high" decoding="async" class="aligncenter size-full wp-image-134821" src="https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine.png" alt="HSL Creatine" width="1000" height="736" srcset="https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine.png 1000w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-400x294.png 400w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-538x396.png 538w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-256x188.png 256w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-300x221.png 300w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-150x110.png 150w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-480x353.png 480w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-600x442.png 600w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-360x265.png 360w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-262x193.png 262w, https://www.lifespan.io/wp-content/uploads/2025/01/HSL-Creatine-555x408.png 555w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--e7d1f824ee9e21 a {background-color:#1e4fba;}.rb--e7d1f824ee9e21 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--e7d1f824ee9e21"><a href="https://www.lifespan.io/how-you-can-help/" target="_self">Yes I will donate❤️</a></div></div></div> </div> <h2 style="text-align: justify;"><b>Literature</b></h2> <p style="text-align: justify;">[1] Zhang, Z., Fang, Y., He, Y., Farag, M. A., Zeng, M., Sun, Y., Peng, S., Jiang, S., Zhang, X., Chen, K., Xu, M., Han, Z., &amp; Zhang, J. (2024). Bifidobacterium animalis Probio-M8 improves sarcopenia physical performance by mitigating creatine restrictions imposed by microbial metabolites. NPJ biofilms and microbiomes, 10(1), 144.</p> <p style="text-align: justify;">[2] Cohen, S., Nathan, J. A., &amp; Goldberg, A. L. (2015). Muscle wasting in disease: molecular mechanisms and promising therapies. Nature reviews. Drug discovery, 14(1), 58–74.</p> <p style="text-align: justify;">[3] Zhong, Z., Tang, H., Shen, T., Ma, X., Zhao, F., Kwok, L. Y., Sun, Z., Bilige, M., &amp; Zhang, H. (2022). Bifidobacterium animalis subsp. lactis Probio-M8 undergoes host adaptive evolution by glcU mutation and translocates to the infant&#8217;s gut via oral-/entero-mammary routes through lactation. <i>Microbiome</i>, <i>10</i>(1), 197.</p> <p style="text-align: justify;">[4] Zhao, F., Guo, Z., Kwok, L. Y., Zhao, Z., Wang, K., Li, Y., Sun, Z., Zhao, J., &amp; Zhang, H. (2023). Bifidobacterium lactis Probio-M8 improves bone metabolism in patients with postmenopausal osteoporosis, possibly by modulating the gut microbiota. European journal of nutrition, 62(2), 965–976.</p> <p style="text-align: justify;">[5] Sun, H., Zhao, F., Liu, Y., Ma, T., Jin, H., Quan, K., Leng, B., Zhao, J., Yuan, X., Li, Z., Li, F., Kwok, L. Y., Zhang, S., Sun, Z., Zhang, J., &amp; Zhang, H. (2022). Probiotics synergized with conventional regimen in managing Parkinson&#8217;s disease. <i>NPJ Parkinson&#8217;s disease</i>, <i>8</i>(1), 62.</p> <p style="text-align: justify;">[6] Kuffa, P., Pickard, J. M., Campbell, A., Yamashita, M., Schaus, S. R., Martens, E. C., Schmidt, T. M., Inohara, N., Núñez, G., &amp; Caruso, R. (2023). Fiber-deficient diet inhibits colitis through the regulation of the niche and metabolism of a gut pathobiont. <i>Cell host &amp; microbe</i>, <i>31</i>(12), 2007–2022.e12.</p> <p style="text-align: justify;">[7] Casciola, R., Leoni, L., Cuffari, B., Pecchini, M., Menozzi, R., Colecchia, A., &amp; Ravaioli, F. (2023). Creatine Supplementation to Improve Sarcopenia in Chronic Liver Disease: Facts and Perspectives. Nutrients, 15(4), 863.</p> <p style="text-align: justify;">[8] Watson, M. D., Cross, B. L., &amp; Grosicki, G. J. (2021). Evidence for the Contribution of Gut Microbiota to Age-Related Anabolic Resistance. Nutrients, 13(2), 706.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134819&quot; data-voice=&quot;en-US-CoraNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134819&amp;voice=en-US-CoraNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

A Gut Metabolite Reduces Senescence and Inflammation

The researchers cultured healthy fibroblasts in the presence of media collected from either control senescent cells or those treated with Urolithin A and found that the latter scenario caused less paracrine senescence. “Urolithin A has generated a lot of excitement in the last several years based on its potential use as an anti-aging therapeutic,” said Dr. Julie Andersen of the Buck Institute for Research on Aging, a co-author of this study and the earlier one showing that Urolithin A increases

Cyclarity Launches Human Trial for Atherosclerosis

<p style="text-align: justify;">Cyclarity Therapeutics, a biotechnology company based at the Buck Institute in California, has launched its first human clinical trial.</p> <p style="text-align: justify;">Its primary candidate <a href="https://cyclaritytx.com/our-science/">cyclodextrin drug, UDP-003</a>, focuses on 7-ketocholesterol, an oxidized cholesterol variant that builds up in cells as we age. Atherosclerosis involves the accumulation of plaque within arteries, and it primarily results from this oxidized form of cholesterol.</p> <p style="text-align: justify;">Heart disease is the leading cause of death worldwide. If successful, this drug could potentially help 70 to 80 percent of people that have heart disease and are at risk of having heart attacks.</p> <p style="text-align: justify;">Current treatment of heart disease includes lifestyle and dietary interventions, statins, and surgery. However, these are not that effective, and there is currently no effective way to reverse the condition. If UDP-003 is a success in the coming years, it will be a game changer.</p> <p style="text-align: justify;">Not only will it transform how we treat heart disease, it will be a clear demonstration of how tackling the root causes of aging can lead to proper solutions to age-related diseases.</p> <h2 style="text-align: justify;"><b>Trials and tribulations</b></h2> <p style="text-align: justify;">The original plan had been to launch the trials in Cambridge, UK working with the MHRA (similar to the FDA in the USA), but, unfortunately, there were setbacks.</p> <p style="text-align: justify;">Regular readers may recall our last interview with <a href="https://www.lifespan.io/news/solving-atherosclerosis-the-small-but-mighty-molecule/">Dr. Matthew O’ Connor from Cyclarity</a>, CEO of Scientific Affairs, where he explained the delay:</p> <blockquote> <p style="text-align: justify;">The bad thing is that post Brexit, it seems that the MHRA has gotten a bit backlogged and isn’t able to keep up with our current demands on their time. It takes too long to get meetings and responses to applications currently. We’ve had to take our first human clinical trial to Australia, where it’s a faster, more streamlined, and cheaper process.</p> </blockquote> <p style="text-align: justify;">While this has led to a delay in starting trials for this potentially transformative therapy, it is great to see it finally moving forward.</p> <p style="text-align: justify;">Dr. Matthew O’ Connor was previously the Vice President of Research at the SENS Research Foundation for nine years (now the LRI, of which Lifespan.io is part), where initial research for what was to become UDP-003 was conducted. This trial is a proud moment for both Cyclarity and our organization.</p> <h2 style="text-align: justify;"><b>Australia is leading the charge</b></h2> <p style="text-align: justify;">This research will now take place at CMAX, a leading clinical research center in Australia, in partnership with Monash University. The trials will proceed under the guidance of <a href="https://www.linkedin.com/in/stephen-j-nicholls/">Dr. Stephen Nicholls</a>, the Director of the Monash Victorian Heart Institute in Melbourne and a Professor of Cardiology at Monash University.</p> <p style="text-align: justify;">In the <a href="https://www.lifespan.io/news/cyclarity-therapeutics-secures-approval-for-clinical-trial/">recent Cyclarity press release</a>, Dr. Matthew O’Connor said: “We are excited to be working with Dr. Nicholls on a groundbreaking advancement in cardiovascular care. As we advance into being a clinical stage company, Cyclarity is focused on bringing truly disease-modifying treatments for the world’s deadliest disease into reality.”</p> <p style="text-align: justify;">The Phase 1 clinical study will include a section featuring single ascending dose and multiple ascending dose methodologies as well as a unique segment involving 12 patients suffering from acute coronary syndrome.</p> <p style="text-align: justify;">This trial is intended to assess the safety of UDP-003 in patients with pre-existing plaque and to collect initial insights on its efficacy.</p> <p style="text-align: justify;">Cyclarity has already finished the manufacturing process for the human-quality drug material in what’s known as the Current Good Manufacturing Practice (the <a href="https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations">CGMP</a>). They have human-grade material packaged and in sterile, single-use vials ready for patients to receive.</p> <p style="text-align: justify;">Thorough studies necessary for investigational new drug approval have been completed, showing no expected toxicity issues and ensuring a safe route for clinical advancement. All essential documents for trial authorization have been submitted and accepted, which means that the clinical trial should commence in the very near future.</p> <p style="text-align: justify;">We will be interviewing Dr. Matthew O’ Conner from Cyclarity and finding out more about this exciting development, so stay tuned for that in the next week. Finally, we wish to congratulate the Cyclarity team on this important milestone for our field. Perhaps this will lead to more acceptance of the idea that to tackle age-related diseases, we need to tackle the <a href="https://www.lifespan.io/topic/aging/">underlying reasons we age</a>.</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--99ec2b67e31827 a {background-color:#1e4fba;}.rb--99ec2b67e31827 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--99ec2b67e31827"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134800&quot; data-voice=&quot;en-US-BrandonNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134800&amp;voice=en-US-BrandonNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Intermittent Fasting Improves Coordination in Mice

<p style="text-align: justify;">Researchers have discovered that intermittent fasting <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/acel.14476">increases myelin in aged mice, leading to better neural function and coordination.</a></p> <h2 style="text-align: justify;"><b>Crucial proteins and a well-known intervention</b></h2> <p style="text-align: justify;">Normally, neuronal axons are coated in a protein sheath made of myelin, which is necessary for their proper function [1]. Myelination is most known to be impeded by multiple sclerosis, but it also decreases with aging [2]. It is predominantly formed from two key proteins, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) [3], and previous work has found that upregulating the expression of these proteins has a beneficial effect on myelination [4].</p> <p style="text-align: justify;">Other work has found that myelination can be affected by diet and nutrition [5]. However, that work did not focus on these researchers&#8217; chosen intervention: intermittent fasting, which has been found in substantial previous research to have metabolic and anti-inflammatory benefits, particularly in the context of aging [6].</p> <h2 style="text-align: justify;"><b>Fasting for 18 hours a day</b></h2> <p style="text-align: justify;">For their experiments, the researchers used three groups of mice: ten young mice, ten older mice, and eight older mice that had undergone intermittent fasting fof ten weeks, in which they were only allowed to eat for six hours a day. The researchers first began by testing overall markers of physical function: on the wire hanging test, the fasting mice were able to hold on for longer than the old control group, and they trended towards being able to run faster and longer than this group as well.</p> <p style="text-align: justify;">In a balance beam test, the fasting proved exceptionally potent: the fasting group was able to perform just as well as the young mice, far outpacing their same-aged counterparts. However, cognitive function was found to be unaffected: there was no benefit according to a Y maze test.</p> <h2 style="text-align: justify;"><b>Stronger motor signals</b></h2> <p style="text-align: justify;">A closer look at the mice&#8217;s muscles may have revealed why. While the maximum electrical signal strength going from the nerves to the muscles was not significantly affected, the treatment group had higher average signal strength. Looking at the frequency ranges involved revealed that the treatment group could exert more force and could react more quickly than similarly aged mice that were fed freely.</p> <p style="text-align: justify;">The brain was affected as well. Measuring whole-brain connectivity, the researchers found that the brains of the treated mice were less connected in ten areas but more connected in seven, particularly in places related to motor function and sensory input. Comparing these connection differences to the physical tests, the researchers concluded that these changes may also be responsible for the improvements they found.</p> <h2 style="text-align: justify;"><b>Myelin was directly improved</b></h2> <p style="text-align: justify;">Finally, the researchers looked directly at the myelin in the brain. Interestingly, and possibly of concern, the fasting group had reduced axonal diameters compared to the aged control group, suggesting an increase in degeneration. However, they had substantially more myelin, particularly on their smaller axons. These findings were true for both motor and non-motor portions of the brain, and the researchers note that this has been documented to occur in other animals, including people, who are recovering from demyelinating diseases [5].</p> <p style="text-align: justify;">Both MBP and MAG were positively affected. The treated mice had significantly more of both proteins in both of the tested areas, although there was no significant increase in MAG in the motor cortex. Myelinated fibers were found to trend towards being more common and longer in the fasting group. Overall, these results suggest that fasting somewhat changes the brain, and the researchers hold that these changes are beneficial.</p> <p style="text-align: justify;">While this is only a mouse study, it is in line with previous research showing that such dietary interventions may have beneficial effects on the brain. Furthermore, while it may not be appropriate for everyone, intermittent fasting is a freely available intervention. More studies may reveal whether or not it has beneficial effects on the myelin, and muscle coordination, of older people.</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--99ec2b67e354f8 a {background-color:#1e4fba;}.rb--99ec2b67e354f8 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--99ec2b67e354f8"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <h2 style="text-align: justify;"><b>Literature</b></h2> <p style="text-align: justify;">[1] Almeida, R. G., &amp; Lyons, D. A. (2017). On myelinated axon plasticity and neuronal circuit formation and function. <i>Journal of Neuroscience</i>, <i>37</i>(42), 10023-10034.</p> <p style="text-align: justify;">[2] Nickel, M., &amp; Gu, C. (2018). Regulation of central nervous system myelination in higher brain functions. <i>Neural plasticity</i>, <i>2018</i>(1), 6436453.</p> <p style="text-align: justify;">[3] Deng, S., Shu, S., Zhai, L., Xia, S., Cao, X., Li, H., &#8230; &amp; Xu, Y. (2023). Optogenetic stimulation of mPFC alleviates white matter injury‐related cognitive decline after chronic ischemia through adaptive myelination. <i>Advanced science</i>, <i>10</i>(5), 2202976.</p> <p style="text-align: justify;">[4] Zhang, Q., Zhu, W., Xu, F., Dai, X., Shi, L., Cai, W., &#8230; &amp; Hu, X. (2019). The interleukin-4/PPARγ signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury. <i>PLoS biology</i>, <i>17</i>(6), e3000330.</p> <p style="text-align: justify;">[5] Langley, M. R., Triplet, E. M., &amp; Scarisbrick, I. A. (2020). Dietary influence on central nervous system myelin production, injury, and regeneration. <i>Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease</i>, <i>1866</i>(7), 165779.</p> <p style="text-align: justify;">[6] De Cabo, R., &amp; Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. <i>New England Journal of Medicine</i>, <i>381</i>(26), 2541-2551.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134792&quot; data-voice=&quot;en-US-BrandonNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134792&amp;voice=en-US-BrandonNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Cyclarity Therapeutics Secures Approval for Clinical Trial

<p style="text-align: justify;" align="justify"><strong>Cyclarity Therapeutics is pleased to announce regulatory approval to begin its first-in-human clinical trial.</strong> The trial will be conducted at CMAX, one of Australia’s leading clinical research centers, in partnership with Monash University. This effort will be led by Dr. Stephen Nicholls of the Victorian Heart Institute (VHI), a distinguished leader in cardiovascular medicine. In addition to a traditional SAD/MAD phase 1 trial, the authorization includes an allowance to enroll 12 patients with Acute Coronary Syndrome (ACS) to assess the safety of UDP-003 in individuals with plaque buildup, as well as to explore anecdotal evidence of efficacy. This represents a critical first step in evaluating the potential impact of our therapy in a population with high unmet need.</p> <p style="text-align: justify;"></p> <p style="text-align: justify;" align="justify"><strong>Key performance indicators (KPIs):</strong></p> <ul style="text-align: justify;"> <li><strong>Clinical Trial Material (CTM):</strong> Manufacture is complete, with all supporting documentation and analysis finalized. UDP-003 is in vials and ready for administration to human participants.</li> <li><strong>Investigational New Drug (IND) Enabling Studies:</strong> All studies have been successfully completed with no predicted toxicological liabilities, ensuring a safe path forward.</li> <li><strong>Clinical readiness:</strong> All materials necessary for clinical trial authorization have been submitted and are in place.</li> </ul> <p style="text-align: justify;" align="justify">This milestone marks a significant moment for Cyclarity as the trial joins Dr. Nicholls&#8217; legacy of innovative clinical research. His previous work includes the SATURN trial for Crestor in the early 2000s, the CLEAR Outcomes trial in the 2020s that introduced bempedoic acid as a statin alternative, and the recent Muvalaplin trial targeting Lp(a), a major innovation in cardiovascular health.</p> <p style="text-align: justify;" align="justify">“We are excited to be working with Dr. Nicholls on a groundbreaking advancement in cardiovascular care,” said CEO of Scientific Affairs Matthew O’Connor. “As we advance into being a clinical stage company, Cyclarity is focused on bringing truly disease-modifying treatments for the world’s deadliest disease into reality.”</p> <p style="text-align: justify;" align="justify">We deeply appreciate the support we’ve received to reach this important stage and invite you to stay tuned as we continue to push the boundaries of therapeutic development. For more information, please contact <a href="mailto:[email protected]">[email protected]</a> or visit <a href="https://cyclaritytx.com/" rel="nofollow"><u>https://cyclaritytx.com/</u></a>.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134766&quot; data-voice=&quot;en-US-JennyNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134766&amp;voice=en-US-JennyNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Precision Targeting of Senescent Cells

<p style="text-align: justify;">In a journal called <i>Small</i>, researchers have described <a href="https://onlinelibrary.wiley.com/doi/10.1002/smll.202405732">a new targeting mechanism for delivering senolytic compounds where they need to go</a>.</p> <h2 style="text-align: justify;"><b>Finding the right nanoparticle</b></h2> <p style="text-align: justify;"><div class="wpv-grid grid-1-1 wpv-first-level unextended animation-from-left"><div class="topic-box-item" style="background-color:#fff"><a href="https://www.lifespan.io/topic/cellular-senescence/" class="topic-thumb-link"><div class="topic-box-thumb-wrap topic-thumb-align-left"><div class="topic-box-thumb" style="background:url(https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484.jpg) no-repeat center center;background-size: contain;"><img fetchpriority="high" decoding="async" width="1000" height="666" src="https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484.jpg" class="attachment-full size-full wp-post-image" alt="Cellular Senescence is one of the proposed reasons we age." srcset="https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484.jpg 1000w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-400x266.jpg 400w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-595x396.jpg 595w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-256x170.jpg 256w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-300x200.jpg 300w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-150x100.jpg 150w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-480x320.jpg 480w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-600x400.jpg 600w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-360x240.jpg 360w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-262x174.jpg 262w, https://www.lifespan.io/wp-content/uploads/2021/05/shutterstock_1615272484-555x370.jpg 555w" sizes="(max-width: 1000px) 100vw, 1000px" /></div></div></a><a class="topic-info-link" href="https://www.lifespan.io/topic/cellular-senescence/"><div class="topic-box-title">Why we Age: Cellular Senescence</div><div class="topic-box-desc">As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...<br><span class="topi-read-more">Read More</span></div></a></div></div><style>.institute-box-title,.page-contribution-history #main-content .entry-content,.page-manage-saved-cards #main-content .entry-content,.page-manage-subscriptions #content,.reference-box-title,.topic-box-title{padding-top:10px}.blog-page-wrapper #sidebar #an-mailchimp-email-2:after,.facebook-feed-wrapper:after,.grid-1-2 .topic-box-item:after,.leaf-grid-row:after,.post-actions-wrapper:after,.reference-box-item:after,.topic-box-item:after{content:'';display:table;clear:both}.grid-1-1,.grid-1-2,.grid-1-3,.grid-1-4,.grid-1-5,.grid-1-6,.grid-2-3,.grid-2-5,.grid-3-4,.grid-3-5,.grid-4-5,.grid-5-6{padding:0 15px;float:left;box-sizing:border-box}.wpv-grid img{max-width:100%;display:block;height:auto}.wpv-grid.grid-1-1{width:100%;clear:both}.institute-box-item,.reference-box-item,.topic-box-item{max-width:300px;margin-bottom:30px}.institute-box-thumb-wrap .institute-box-thumb,.reference-box-thumb-wrap .reference-box-thumb,.topic-box-thumb-wrap .topic-box-thumb{display:block;border:15px solid #fff;width:100%;height:150px;box-sizing:border-box}.topic-box-thumb-wrap{border:1px solid #ddd}.institute-box-thumb-wrap .institute-box-thumb img,.reference-box-thumb-wrap .reference-box-thumb img,.topic-box-thumb-wrap .topic-box-thumb img{opacity:0;max-width:100%;height:auto;visibility:hidden}.reference-box-item,.topic-box-item{max-width:100%;border:1px solid #ddd;padding:15px}.reference-box-thumb-wrap,.topic-box-thumb-wrap{max-width:300px;border:none}.reference-box-thumb-wrap .reference-box-thumb,.topic-box-thumb-wrap .topic-box-thumb{height:inherit;padding:0;border:none;margin:30px 0 15px;height:inherit}.reference-box-title,.reference-box-title a,.topic-box-title,.topic-box-title a{font-weight:700;text-transform:uppercase;font-size:20px;color:#4d4d4d!important;margin-bottom:5px;display:block}.reference-box-item a.reference-info-link,.topic-box-item a.topic-info-link{display:block;color:#565656;text-decoration:none}.reference-box-desc,.topic-box-desc{margin-bottom:10px;padding-bottom:10px;border-bottom:1px solid #ddd}.reference-box-thumb-wrap.reference-thumb-align-left,.topic-box-thumb-wrap.topic-thumb-align-left{float:left;margin-right:30px;width:40%;margin-bottom:10px}.topic-box-desc{border-bottom:none;text-align:justify}@media (max-width:958px){.leaf-template .grid-1-2:last-child,.leaf-template .grid-1-3:last-child,.leaf-template .grid-1-4:last-child,.leaf-template .grid-1-5:last-child,.leaf-template .grid-1-6:last-child,.leaf-template .grid-2-3:last-child,.leaf-template .grid-2-5:last-child,.leaf-template .grid-3-4:last-child,.leaf-template .grid-3-5:last-child,.leaf-template .grid-4-5:last-child,.leaf-template .grid-5-6:last-child,.leaf-template .site .grid-1-1,.leaf-template .site .grid-1-1:last-child{margin-bottom:0}}@media all and (max-width:767px){.reference-box-thumb-wrap.reference-thumb-align-left,.reference-box-thumb-wrap.reference-thumb-align-right,.topic-box-thumb-wrap.topic-thumb-align-left,.topic-box-thumb-wrap.topic-thumb-align-right{width:100%;float:none;margin:0}}</style></p> <p style="text-align: justify;">This paper begins with a discussion of the well-known features of cellular senescence and laments that, despite all the work done in this area, no senolytic has yet been approved for clinical use. The researchers provide evidence that this is due to both efficacy and targeting: senolytics do not always solely affect senescent cells [1].</p> <p style="text-align: justify;">Previous work has focused on using galactose as a carrier for such potential drugs [2], as senescent cells are characterized by the presence of SA-β-gal, a compound that naturally cleaves galactose. This approach has, in early studies, been found to reduce the toxicity of navitoclax, the senolytic that is the focus of this study [1].</p> <p style="text-align: justify;">However, much of that previous work was focused on encapsulating porous silica with galactose as a nanocarrier for the drug, and these researchers note that porous silica can be toxic [3]. Trying to directly modify drugs with galactose changes is also not perfect, as this process changes their structure and is difficult to accomplish [4].</p> <h2 style="text-align: justify;"><b>The soap approach</b></h2> <p style="text-align: justify;">Instead of silica, these researchers chose to encapsulate their drug in amphiphilic micelles, which are very similar to soap bubbles and have been previously examined in drug delivery [5]. Here, the micelles have the water-attracted (hydrophilic) portion facing outwards and holding the galactose, with the water-repellent (hydrophobic) portion facing inwards to contain the navitoclax. The researchers go into detail regarding the chemistry of how they accomplished this, using a variety of branches extending from the central component and then assembling those molecules together to form a bubble.</p> <p style="text-align: justify;"><img decoding="async" class="aligncenter size-full wp-image-134758" src="https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures.jpg" alt="Soap structures" width="1367" height="733" srcset="https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures.jpg 1367w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-400x214.jpg 400w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-739x396.jpg 739w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-256x137.jpg 256w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-300x161.jpg 300w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-1024x549.jpg 1024w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-150x80.jpg 150w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-480x257.jpg 480w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-600x322.jpg 600w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-360x193.jpg 360w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-262x140.jpg 262w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-555x298.jpg 555w, https://www.lifespan.io/wp-content/uploads/2025/01/Soap-structures-1140x611.jpg 1140w" sizes="(max-width: 1367px) 100vw, 1367px" /></p> <p style="text-align: justify;">Of these three approaches, the branched variant was found to be the most effective, as shown by an in vitro test using fluorescent Nile Red dye. Furthermore, the bubble was found to be protective: in the absence of β-galactosidase, only 6% of the total fluorescence was reduced 24 hours after exposure, while in its presence, 50% of it was gone within 6 hours and 90% within 24 hours.</p> <h2 style="text-align: justify;"><b>Effective in cells</b></h2> <p style="text-align: justify;">The researchers then tested their compound against actual senescent cells, specifically cells derived from lung cancer (A549) and melanoma (SK-MEL-103) lines. The senolytic index, which measures efficacy versus off-target effects, was much stronger in the encapsulated variant versus raw navitoclax alone: the micelle-encapsulated drug was more selective against senescent cells, particularly in the A549 line.</p> <p style="text-align: justify;"><img decoding="async" class="aligncenter size-full wp-image-134759" src="https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness.png" alt="Micelle effectiveness" width="1000" height="1116" srcset="https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness.png 1000w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-358x400.png 358w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-355x396.png 355w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-229x256.png 229w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-269x300.png 269w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-918x1024.png 918w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-150x167.png 150w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-480x536.png 480w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-600x670.png 600w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-360x402.png 360w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-262x292.png 262w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-555x619.png 555w, https://www.lifespan.io/wp-content/uploads/2025/01/Micelle-effectiveness-300x335.png 300w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <p style="text-align: justify;">However, this paper is only a cellular study, and there were no animals involved. Furthermore, the experiments were conducted solely on cell lines derived from cancer, and it has yet to be experimentally determined how other cells or living organisms might respond to these micelles in the body. Still, this paper serves as a useful proof of concept, explaining how a drug can be targeted to the cells that need it most.</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--a566f460888143 a {background-color:#1e4fba;}.rb--a566f460888143 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--a566f460888143"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <h2 style="text-align: justify;"><b>Literature</b></h2> <p style="text-align: justify;">[1] González‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson III, J. R., González‐López, C., &#8230; &amp; Muñoz‐Espín, D. (2020). Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. <i>Aging cell</i>, <i>19</i>(4), e13142.</p> <p style="text-align: justify;">[2] Muñoz‐Espín, D., Rovira, M., Galiana, I., Giménez, C., Lozano‐Torres, B., Paez‐Ribes, M., &#8230; &amp; Serrano, M. (2018). A versatile drug delivery system targeting senescent cells. <i>EMBO molecular medicine</i>, <i>10</i>(9), e9355.</p> <p style="text-align: justify;">[3] Lin, Y. S., &amp; Haynes, C. L. (2010). Impacts of mesoporous silica nanoparticle size, pore ordering, and pore integrity on hemolytic activity. <i>Journal of the American Chemical Society</i>, <i>132</i>(13), 4834-4842.</p> <p style="text-align: justify;">[4] Guerrero, A., Guiho, R., Herranz, N., Uren, A., Withers, D. J., Martínez‐Barbera, J. P., &#8230; &amp; Gil, J. (2020). Galactose‐modified duocarmycin prodrugs as senolytics. <i>Aging Cell</i>, <i>19</i>(4), e13133.</p> <p style="text-align: justify;">[5] Parshad, B., Prasad, S., Bhatia, S., Mittal, A., Pan, Y., Mishra, P. K., &#8230; &amp; Fruk, L. (2020). Non-ionic small amphiphile based nanostructures for biomedical applications. <i>RSC advances</i>, <i>10</i>(69), 42098-42115.</p> <div id="playht-shortcode" data-shortcode=""></div>

Receiving Caloric Restriction Benefits Without Practicing It

<p style="text-align: justify;">In a new study, researchers have found that lithocholic acid, a metabolite found in the serum of calorically restricted mice, <a href="https://pubmed.ncbi.nlm.nih.gov/39695227/">can mimic the effects of caloric restriction</a> [1].</p> <h2 style="text-align: justify;"><b>Restricting calories to live longer</b></h2> <p style="text-align: justify;"><a href="https://www.lifespan.io/topic/what-is-caloric-restriction/">Caloric restriction</a> without malnutrition improves healthspan and extended lifespan in multiple model organisms and has been found to have health benefits in human studies. <a href="https://www.lifespan.io/?s=caloric+restriction">We have covered the many benefits of caloric restriction</a> on longevity and healthspan, including a recently published interview in which we discussed <a href="https://www.lifespan.io/news/rozalyn-anderson-explains-caloric-restriction/">one of the longest-running caloric restriction experiments on monkeys</a>.</p> <h2 style="text-align: justify;"><b>Mimicking caloric restriction</b></h2> <p style="text-align: justify;">Restricting calories changes many aspects of an organism’s metabolism [2]. One of its well-documented effects is the activation of AMP-activated protein kinase (AMPK). AMPK is an essential regulator of multiple signaling pathways, including aging-related pathways and cellular processes, and mediates many of these beneficial effects [3]. In this study, the researchers used AMPK as a proxy to identify metabolites that mimic caloric restriction.</p> <p style="text-align: justify;">The researchers subjected mice to 4 months of caloric restriction. Then, they treated a few cell lines with serum from calorically restricted mice. The serum activated AMPK in those cell lines, suggesting that this serum mimicked the effects of caloric restriction. The activation of AMPK was also possible in the liver and muscle cells of normally fed mice treated with the serum of calorically restricted mice.</p> <h2 style="text-align: justify;"><b>Finding ‘the one’</b></h2> <p style="text-align: justify;">Being able to mimic the effects of caloric restriction without restricting caloric intake is an intriguing idea. However, using a whole serum from mice to achieve it is not a practical solution, especially since, most likely, only one or a few molecules from the serum are responsible for the effect of AMPK activation. The researchers went on a quest to identify those molecules.</p> <p style="text-align: justify;">They employed mass spectrometry-based approaches to identify over a thousand specific metabolites in the serum, and almost seven hundred that were altered by caloric restriction. After performing a few more tests to narrow the list, they performed a screen on cell cultures using AMPK activation as a biomarker.</p> <p style="text-align: justify;">In the initial screening, the researchers identified six metabolites that increased after caloric restriction and activated AMPK in cell cultures. However, the concentrations needed to activate AMPK by most of those metabolites were too high to be used in physiological conditions.</p> <p style="text-align: justify;">Only one of the identified metabolites, lithocholic acid (LCA), one of the bile acids (but not its derivatives), activated AMPK when administered at a concentration similar to that in the serum.</p> <h2 style="text-align: justify;"><b>Late-life intervention</b></h2> <p style="text-align: justify;">The researchers asked whether LCA can improve aging-related phenotypes when administered later in life. To test it, they gave aged mice LCA for one month. They noted that while mice and humans differ in their bile acid composition, LCA concentrations are similar in both species [4, 5].</p> <p style="text-align: justify;">The authors observed many improvements following LCA treatment in mice, including increased running distance, duration, and grip strength, and positive impact on other molecular measures, such as NAD+ levels, mitochondrial content, mitochondrial respiratory function, glucose tolerance, and insulin resistance.</p> <p style="text-align: justify;">LCA also didn’t cause muscle loss, a phenotype observed in mice and humans when restricting calories [6], suggesting that LCA treatment may be more beneficial. Additionally, muscle regeneration after damage was accelerated in aged mice following the LCA treatment.</p> <h2 style="text-align: justify;"><b>Extending lifespan</b></h2> <p style="text-align: justify;">As AMPK is an essential player in mediating lifespan extension [3], the researchers tested if LCA can mimic the effects of caloric restriction and extend lifespan in the model organisms <i>C. elegans </i>(worms) and<i> D. melanogaster </i>(fruit flies).</p> <p style="text-align: justify;">LCA treatment in worms and flies activated AMPK and extended their mean lifespans. In hermaphroditic <i>C. elegans</i>, lifespan was extended from 22 to 27 days. Lifespan extension from LCA was similar to that of caloric restriction and consistent with previous reports showing LCA-mediated lifespan extension in flies [7]: from 47 to 52 days in males and from 52 to 56 days in females.</p> <p style="text-align: justify;">The positive effect of LCA treatment was also evident in healthspan markers in worms and flies, for example, in a few measurements of resistance to different stresses or NAD+ levels. The activity of AMPK was necessary for those improvements since inactivating the AMPK gene in worms or flies abrogated those anti-aging effects.</p> <p style="text-align: justify;">The effects of LCA were more modest in mice, resulting in “a consistent, albeit nonsignificant, increase in median lifespan” when LCA was started at one year of age. Depending on the cohort, the increase was between 5.1% and 9.6% for male and between 8.3% and 12.5% for female mice.</p> <p style="text-align: justify;">The authors suggest that altering the LCA dose or the age at which LCA was administered might improve lifespan extension.</p> <h2 style="text-align: justify;"><b>The role of gut microbes</b></h2> <p style="text-align: justify;">The authors point to gut microbes’ role in LCA metabolism. LCA precursors are secreted from the liver to the intestine, where microbes, specifically by<i> Lactobacillus</i>, <i>Clostridium</i>, and <i>Eubacterium</i> species<i>, </i>convert it to LCA. Those microbes are known to be increased after caloric restriction [8, 9].</p> <p style="text-align: justify;">“It is reasonable to suggest that the LCA increase that occurs during CR may be caused by changes in these gut microbes.” Current and previous research supports the role of gut microbes in LCA metabolism when calories are restricted. The authors report detecting higher concentrations of LCA in the feces of calorically restricted mice. This was not observed in mice lacking gut microbes or with disrupted gut microbiome due to antibiotic treatment. Similarly, transplanting feces from calorically restricted mice into germ-free mice or antibiotic-treated mice caused an increase in LCA levels, which was higher than when feces were transplanted from normally fed mice.</p> <p style="text-align: justify;">The role of <i>Clostridioides </i>in increasing LCA levels is also supported by human research, as healthy centenarians with high <i>Clostridioides</i> levels also have high levels of LCA [10].</p> <p style="text-align: justify;">The authors summarize that their research “provided multiple lines of evidence to show that LCA acts as a CRM [caloric restriction mimetic], recapitulating the effects of CR, including AMPK activation and rejuvenating and anti-aging effects.“</p> <p style="text-align: justify;">While their research was conducted on model systems, they point to a previous study that observed that LCA was observed to be increased in the serum of healthy humans following 36 hours of fasting, suggesting a link between LCA and fasting in humans [11].</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--17206ec6562ec5 a {background-color:#1e4fba;}.rb--17206ec6562ec5 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--17206ec6562ec5"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <h2 style="text-align: justify;"><b>Literature</b></h2> <p style="text-align: justify;">[1] Qu, Q., Chen, Y., Wang, Y., Long, S., Wang, W., Yang, H. Y., Li, M., Tian, X., Wei, X., Liu, Y. H., Xu, S., Zhang, C., Zhu, M., Lam, S. M., Wu, J., Yun, C., Chen, J., Xue, S., Zhang, B., Zheng, Z. Z., … Lin, S. C. (2024). Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature, 10.1038/s41586-024-08329-5. Advance online publication.</p> <p style="text-align: justify;">[2] Selman, C., Kerrison, N. D., Cooray, A., Piper, M. D., Lingard, S. J., Barton, R. H., Schuster, E. F., Blanc, E., Gems, D., Nicholson, J. K., Thornton, J. M., Partridge, L., &amp; Withers, D. J. (2006). Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiological genomics, 27(3), 187–200.</p> <p style="text-align: justify;">[3] Burkewitz, K., Zhang, Y., &amp; Mair, W. B. (2014). AMPK at the nexus of energetics and aging. Cell metabolism, 20(1), 10–25.</p> <p style="text-align: justify;">[4] Zhao, A., Zhang, L., Zhang, X., Edirisinghe, I., Burton-Freeman, B. M., &amp; Sandhu, A. K. (2021). Comprehensive Characterization of Bile Acids in Human Biological Samples and Effect of 4-Week Strawberry Intake on Bile Acid Composition in Human Plasma. Metabolites, 11(2), 99.</p> <p style="text-align: justify;">[5] Li, M., Wang, S., Li, Y., Zhao, M., Kuang, J., Liang, D., Wang, J., Wei, M., Rajani, C., Ma, X., Tang, Y., Ren, Z., Chen, T., Zhao, A., Hu, C., Shen, C., Jia, W., Liu, P., Zheng, X., &amp; Jia, W. (2022). Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice. Nature communications, 13(1), 2060.</p> <p style="text-align: justify;">[6] Heymsfield, S. B., Yang, S., McCarthy, C., Brown, J. B., Martin, C. K., Redman, L. M., Ravussin, E., Shen, W., Müller, M. J., &amp; Bosy-Westphal, A. (2024). Proportion of caloric restriction-induced weight loss as skeletal muscle. Obesity (Silver Spring, Md.), 32(1), 32–40.</p> <p style="text-align: justify;">[7] Staats, S., Rimbach, G., Kuenstner, A., Graspeuntner, S., Rupp, J., Busch, H., Sina, C., Ipharraguerre, I. R., &amp; Wagner, A. E. (2018). Lithocholic Acid Improves the Survival of Drosophila Melanogaster. Molecular nutrition &amp; food research, 62(20), e1800424.</p> <p style="text-align: justify;">[8] Cai, J., Rimal, B., Jiang, C., Chiang, J. Y. L., &amp; Patterson, A. D. (2022). Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacology &amp; therapeutics, 237, 108238.</p> <p style="text-align: justify;">[9] Fraumene, C., Manghina, V., Cadoni, E., Marongiu, F., Abbondio, M., Serra, M., Palomba, A., Tanca, A., Laconi, E., &amp; Uzzau, S. (2018). Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota. Gut microbes, 9(2), 104–114.</p> <p style="text-align: justify;">[10] Sato, Y., Atarashi, K., Plichta, D. R., Arai, Y., Sasajima, S., Kearney, S. M., Suda, W., Takeshita, K., Sasaki, T., Okamoto, S., Skelly, A. N., Okamura, Y., Vlamakis, H., Li, Y., Tanoue, T., Takei, H., Nittono, H., Narushima, S., Irie, J., Itoh, H., … Honda, K. (2021). Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature, 599(7885), 458–464.</p> <p style="text-align: justify;">[11] Fiamoncini, J., Rist, M. J., Frommherz, L., Giesbertz, P., Pfrang, B., Kremer, W., Huber, F., Kastenmüller, G., Skurk, T., Hauner, H., Suhre, K., Daniel, H., &amp; Kulling, S. E. (2022). Dynamics and determinants of human plasma bile acid profiles during dietary challenges. Frontiers in nutrition, 9, 932937.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134730&quot; data-voice=&quot;en-US-CoraNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134730&amp;voice=en-US-CoraNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Vitalia Co-Founders Announce Split-up

<p style="text-align: justify;">Vitalia co-founders Niklas Anzinger and Laurence Ion today announced that they will be leading two new, separate organizations, <a href="http://cityofviva.com" rel="nofollow">Viva City</a> and <a href="http://infinita.city" rel="nofollow">Infinita City</a>.</p> <p style="text-align: justify;">&#8220;Together, we built Vitalia from the ground up, establishing a foundation that has led us to this exciting new chapter,&#8221; said Anzinger and Ion in a joint statement. &#8220;This decision stems from our shared recognition that our unique perspectives can best flourish in two distinct organizations, each with its own approach. Both companies remain committed to accelerating biomedical innovation, and we look forward to building on our shared legacy in complementary directions.&#8221;</p> <p style="text-align: justify;">Laurence Ion will lead <a href="http://cityofviva.com" rel="nofollow">Viva City</a>, which will concentrate on building a city within a special regulatory zone governed by its residents, to accelerate medical innovation and extend healthy lifespan.</p> <p style="text-align: justify;">Niklas Anzinger will head <a href="http://infinita.city" rel="nofollow">Infinita City</a>, which will concentrate on special regulatory zones as a path to acceleration.</p> <p style="text-align: justify;">&#8220;We extend our gratitude to our community, partners, and investors, whose trust has been pivotal,&#8221; added Anzinger and Ion. &#8220;We are eager to share our next steps and invite you to join us on these parallel journeys. Vitalia will forever continue in our shared memory.&#8221;</p> <p style="text-align: justify;"><b>Joint Statement of Vitalia Co-founders</b></p> <p style="text-align: justify;">We are excited to announce that we are moving forward along two paths to best pursue our respective visions.</p> <p style="text-align: justify;">Together, we built Vitalia from the ground up, establishing a foundation that has led us to this exciting new chapter.</p> <p style="text-align: justify;">Laurence will lead Viva City, which will concentrate on building a city within a special regulatory zone governed by its residents, to accelerate medical innovation and extend healthy lifespan. It can be followed on these new channels: <a href="https://cityofviva.com" rel="nofollow">Website</a> | <a href="https://linktr.ee/CityOfViva" rel="nofollow">Linktree</a></p> <p style="text-align: justify;">Niklas will head Infinita City, which will concentrate on special regulatory zones as a path to acceleration, which can be followed on these new channels: <a href="http://infinita.city" rel="nofollow">Website</a> | <a href="https://linktr.ee/infinitacity" rel="nofollow">Linktree</a></p> <p style="text-align: justify;">This decision stems from our shared recognition that our unique perspectives can best flourish in two distinct organizations, each with its own approach.</p> <p style="text-align: justify;">Both companies remain committed to accelerating biomedical innovation, and we look forward to building on our shared legacy in complementary directions.</p> <p style="text-align: justify;">We extend our gratitude to our community, partners, and investors, whose trust has been pivotal. We are eager to share our next steps and invite you to join us on these parallel journeys.</p> <p style="text-align: justify;">Vitalia will forever continue in our shared memory.</p> <p style="text-align: justify;">Niklas Anzinger &amp; Laurence Ion</p> <p style="text-align: justify;">Vitalia</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--ac653c199d39b4 a {background-color:#1e4fba;}.rb--ac653c199d39b4 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--ac653c199d39b4"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134726&quot; data-voice=&quot;en-US-JennyNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134726&amp;voice=en-US-JennyNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Drinking and Dying: Alcohol as a Risk Factor for Cancer

The advisory, based on the current state of research, calls alcohol &#8220;a leading preventable cause of cancer in the United States, contributing to nearly 100,000 cancer cases and about 20,000 cancer deaths each year.” Alcohol consumption is linked to at least seven cancer types: breast, colorectum, esophagus, liver, mouth, throat, and larynx. “It appears that alcohol is most closely linked to the cancers of all levels of the digestive system, which is expected, as alcohol causes DNA damage,

A Potential Gene Therapy for Hearing Loss

<p style="text-align: justify;">In <i>JCI Insight</i>, researchers have explored the possibility of <a href="https://insight.jci.org/articles/view/182138">using gene therapy to restore a crucial protein and repair hearing loss</a>.</p> <p style="text-align: justify;"><b>Hearing and its failure</b></p> <p style="text-align: justify;">In mammals, afferent neurons, which originate from the inner ear, transform received stimuli (sound waves) into electrical signals [1]. This process is known as mechanoelectrical transduction, and a specific myosin, MYO7A, has been found to be a critical part of it [2]. Problems with the related gene, <i>Myo7a</i>, result in various forms of deafness [3].</p> <p style="text-align: justify;">Knocking this gene out in mature animals has been found to lead to reversion into a nonfunctional state, which is normally found in prenatal animals that have not yet developed the ability to hear [4]. This state is characterized by efferent neurons, which originate from the brain stem rather than inner ear cells, having direct connections to the inner ear that do not exist in functionally hearing animals. As this process also occurs with aging [5], the researchers decided to investigate whether or not directly affecting this gene could lead to hearing restoration in an animal model.</p> <p style="text-align: justify;"><b>Mice that lose their hearing</b></p> <p style="text-align: justify;">The researchers developed a mouse strain that can be triggered to downregulate the <i>Myo7a</i> gene. A few days after this gene was downregulated, mice of both sexes quickly lost their hearing, and by two weeks, the mice were nearly completely deaf at all frequencies, and a large part of their hearing was found to be rewired into the same nonfunctional state found in prehearing and aged animals. <i>Myo7a</i> was not found to affect the afferent neurons themselves, only the efferent innervation of hair cells.</p> <p style="text-align: justify;">Downregulating <i>Myo7a</i> only in the inner hair cells, which directly send signals to the brain, was found to be sufficient to lead to deafness. Downregulating it in the outer hair cells, amplifier cells that are more susceptible to damage and aging, led to deafness as well.</p> <p style="text-align: justify;"><b>Restoration through gene therapy has positive effects</b></p> <p style="text-align: justify;">Injecting the inner ears of these genetically modified mice with an adeno-associated virus (AAV) that restores this protein had positive effects, with many wiring structures being restored to their functional adult versions. However, it did not fully restore the mice&#8217;s hearing to the level of an unaffected control group. Most of the treated animals could hear very loud noises as measured by the auditory brainstem response thresholds for clicker tests (left) and specific pure tone frequencies (right).</p> <p><img fetchpriority="high" decoding="async" class="aligncenter size-full wp-image-134687" src="https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect.png" alt="AAV Hearing Loss Effect" width="926" height="437" srcset="https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect.png 926w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-400x189.png 400w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-745x352.png 745w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-256x121.png 256w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-300x142.png 300w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-150x71.png 150w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-480x227.png 480w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-600x283.png 600w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-360x170.png 360w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-262x124.png 262w, https://www.lifespan.io/wp-content/uploads/2025/01/AAV-Hearing-Loss-Effect-555x262.png 555w" sizes="(max-width: 926px) 100vw, 926px" /></p> <p style="text-align: justify;">Of course, this is a study on a genetically modified mouse model, not aged wild-type animals nor human beings. Further research will need to be done to determine if aged animals can be affected by this kind of gene therapy and whether or not the results can be replicated in people. Furthermore, the effects of this particular AAV approach were weak, but if it can be applied to people, it may be enough to allow hearing aids to function more effectively.</p> <h2><strong>Additional findings</strong></h2> <p style="text-align: justify;">The researchers discovered that MYO7A controls many aspects of hearing loss that were previously hypothesized to occur due to other factors, such as secondary effects from other systems failing or a failure in proper molecular transport. This research also sheds some light on a link between loud noise and deafness: to protect the ears, the brain uses the efferent system to temporarily reduce hearing capability in loud situations [6], and this may be related to the efferent innervation of the inner ear over time.</p> <p style="text-align: justify;">The most critical finding is that the adult cochlea, which processes hearing, is in fact capable of being remodeled through changes in gene expression after birth. True biological hearing restoration, once merely a dream, appears to finally be on the table with this and other recent gene therapy approaches [7], and people with congenital deafness caused by some <i>Myo7a</i> mutations, or people who have lost their hearing through repeated noise exposure, may have an effective treatment in the future.</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--d723312d2a5079 a {background-color:#1e4fba;}.rb--d723312d2a5079 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--d723312d2a5079"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <p style="text-align: justify;"><b>Literature</b></p> <p style="text-align: justify;">[1] Fettiplace, R. (2011). Hair cell transduction, tuning, and synaptic transmission in the mammalian cochlea. <i>Comprehensive Physiology</i>, <i>7</i>(4), 1197-1227.</p> <p style="text-align: justify;">[2] Hasson, T., Gillespie, P. G., Garcia, J. A., MacDonald, R. B., Zhao, Y. D., Yee, A. G., &#8230; &amp; Corey, D. P. (1997). Unconventional myosins in inner-ear sensory epithelia. <i>The Journal of cell biology</i>, <i>137</i>(6), 1287-1307.</p> <p style="text-align: justify;">[3] Weil, D., Küssel, P., Blanchard, S., Lévy, G., Levi-Acobas, F., Drira, M., &#8230; &amp; Petit, C. (1997). The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. <i>Nature genetics</i>, <i>16</i>(2), 191-193.</p> <p style="text-align: justify;">[4] Corns, L. F., Johnson, S. L., Roberts, T., Ranatunga, K. M., Hendry, A., Ceriani, F., &#8230; &amp; Marcotti, W. (2018). Mechanotransduction is required for establishing and maintaining mature inner hair cells and regulating efferent innervation. <i>Nature Communications</i>, <i>9</i>(1), 4015.</p> <p style="text-align: justify;">[5] Lauer, A. M., Fuchs, P. A., Ryugo, D. K., &amp; Francis, H. W. (2012). Efferent synapses return to inner hair cells in the aging cochlea. <i>Neurobiology of aging</i>, <i>33</i>(12), 2892-2902.</p> <p>[6] Fuchs, P. A., &amp; Lauer, A. M. (2019). Efferent inhibition of the cochlea. <i>Cold Spring Harbor perspectives in medicine</i>, <i>9</i>(5), a033530.</p> <p style="text-align: justify;">[7] Amariutei, A. E., Jeng, J. Y., Safieddine, S., &amp; Marcotti, W. (2023). Recent advances and future challenges in gene therapy for hearing loss. <i>Royal Society Open Science</i>, <i>10</i>(6), 230644.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134674&quot; data-voice=&quot;en-US-BrandonNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134674&amp;voice=en-US-BrandonNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Keeping Stem Cells Healthy and Young

<p style="text-align: justify;">A team of researchers has outlined <a href="https://onlinelibrary.wiley.com/doi/10.1111/acel.14446">a new approach that uses mRNA to prevent senescence and strengthen mesenchymal stem cells (MSCs) against aging</a> before they are transplanted into patients.</p> <h2 style="text-align: justify;"><b>Stem cells go bad before they can be used</b></h2> <p style="text-align: justify;">The researchers introduce this study by focusing on the translational problems with MSCs, specifically the propensity of these cells to become senescent during the replication process [1]. The researchers hold that oxidative stress is the key driver of this rapid aging, causing senescence pathways to trigger [2] and mitochondria to become dysfunctional [3], which causes even more oxidative stress.</p> <p style="text-align: justify;">We have previously reported that <a href="https://www.lifespan.io/news/encouraging-hair-growth-by-reducing-senescence/">senolytics might be useful in reducing premature senescence in stem cells before they reach the patient</a>. While this approach has value, particularly in stem cell types that rapidly become senescent in a few replications, it won&#8217;t protect those cells against the patient&#8217;s microenvironment once they are transplanted. While the researchers note that MSCs affect the microenvironment into which they are placed [4], they also note in this study that an oxidative microenvironment is a possible threat to MSCs on top of the existing issues with pre-implantation replication.</p> <p style="text-align: justify;">Therefore, this work focuses on protecting cells before they even begin replicating. Previously, this team had found out that transplanting healthy mitochondria into fibroblasts can prevent fibrosis [5]; here, the researchers encouraged mitochondrial growth by transfecting the stem cells with mRNA for nuclear respiratory factor 1 (NRF1).</p> <h2 style="text-align: justify;"><b>Widespread benefits</b></h2> <p style="text-align: justify;">First, the researchers made sure that their approach was actually increasing mitochondrial mass compared to a control group. Microscopic fluorescence examination and an analysis of the mitochondrial biomarker TFAM agreed that it did after 24 hours: MSCs that were exposed to this mRNA had roughly 50% more mitochondria than the control group, as measured by fluorescence, whether the cells were placed under peroxide-induced oxidative stress or not. Additionally, the mRNA transfection increased NRF1 production by roughly 30 times over controls, although oxidative stress itself also causes NRF1 to increase in response.</p> <p style="text-align: justify;">This NRF1 was found to be effective in blunting markers of oxidative stress under peroxide exposure. While it was not a perfect solution, cells that had been transfected with NRF1 had roughly 25% less oxidative stress as measured by the fluorescence of the MitoSOX reagent. Mitochondrial membrane depolarization, which occurs under oxidative stress, was also reduced in the treatment group. Most critically, these findings were replicated in cells undergoing replicative senescence.</p> <p style="text-align: justify;">NRF1 mRNA treatment also appeared to have benefits related to metabolism. An RNA sequencing analysis revealed that genes related to oxygen usage were significantly upregulated, while glycolysis, a form of anaerobic energy production, was downregulated, signifying a more efficient use of energy. The researchers believe that this primes cells to better handle an environment of increased oxidative stress.</p> <p style="text-align: justify;">This improvement of energy usage was even maintained after exposure to hydrogen peroxide. Under this intense stress, cells normally rely more on glycolysis and less on using oxygen productively. NRF1 transfection reversed nearly all of this change, restoring ATP production and encouraging more proper oxygen use.</p> <p style="text-align: justify;">At relatively high concentrations (400 micromoles), hydrogen peroxide even interferes with the fission and fusion of mitochondria. However, NRF1 protected against this as well, maintaining mitochondrial balance, which was also found to be true in aged, senescent MSCs.</p> <h2 style="text-align: justify;"><b>A better treatment for senescence?</b></h2> <p style="text-align: justify;">NRF1 mRNA had further benefits for senescent cells, reducing key markers of senescence, including the key marker SA-β-gal, and this held true whether the cells were driven senescent by exposure to hydrogen peroxide or by multiple replications. The researchers compared its effects on these biomarkers to the well-studied senolytic ABT263, although this is a senomorphic that changes senescent cells and not a senolytic that kills them.</p> <p style="text-align: justify;">While the researchers found that their mRNA begins to naturally degrade in 48 hours and the resulting increase in mitochondria starts to peter out after 72 hours, this initial time period is likely to be critical for replication and implantation. However, this is still just a cell study. Further work in animals will need to be done before this approach could be considered for use in human beings.</p> <p style="text-align: justify;">Additionally, this work suggests a close tie between cellular senescence and mitochondrial dysfunction. If directly benefiting mitochondria can indeed reduce senescence, this general approach may be useful for other cells, including ones already in the body. However, substantially more work must be done to determine if such an approach is indeed viable.</p> <div class="textwidget"><div class="sep-2"></div> <div class="life-highlight-box lhbox-has-zoom-yes l-hbox-size-large l-hbox-edges-square" style="background-color: #cef0f5;"><div class="l-hbox-lower"><div class="l-hbox-lower-desc" style="color:#000;">We would like to ask you a small favor. <strong>We are a non-profit foundation</strong>, and unlike some other organizations, we have no shareholders and no products to sell you. <strong>All our news and educational content is free</strong> for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, <strong>supports independent journalism</strong> and sustains our future. </div><style>.rb--4ae010b7c41d37 a {background-color:#1e4fba;}.rb--4ae010b7c41d37 a:hover {background-color:#79bcf0;}</style><div class="l-hbox-lower-cta rb--4ae010b7c41d37"><a href="https://www.lifespan.io/how-you-can-help/" target="_self" rel="noopener">Yes I will donate❤️</a></div></div></div> </div> <h2 style="text-align: justify;"><b>Literature</b></h2> <p style="text-align: justify;">[1] McHugh, D., &amp; Gil, J. (2018). Senescence and aging: Causes, consequences, and therapeutic avenues. <i>Journal of Cell Biology</i>, <i>217</i>(1), 65-77.</p> <p style="text-align: justify;">[2] Weng, Z., Wang, Y., Ouchi, T., Liu, H., Qiao, X., Wu, C., &#8230; &amp; Li, B. (2022). Mesenchymal stem/stromal cell senescence: hallmarks, mechanisms, and combating strategies. <i>Stem Cells Translational Medicine</i>, <i>11</i>(4), 356-371.</p> <p style="text-align: justify;">[3] Miwa, S., Kashyap, S., Chini, E., &amp; von Zglinicki, T. (2022). Mitochondrial dysfunction in cell senescence and aging. <i>The Journal of clinical investigation</i>, <i>132</i>(13).</p> <p style="text-align: justify;">[4] Song, N., Scholtemeijer, M., &amp; Shah, K. (2020). Mesenchymal stem cell immunomodulation: mechanisms and therapeutic potential. <i>Trends in pharmacological sciences</i>, <i>41</i>(9), 653-664.</p> <p style="text-align: justify;">[5] Baudo, G., Wu, S., Massaro, M., Liu, H., Lee, H., Zhang, A., &#8230; &amp; Blanco, E. (2023). Polymer-functionalized mitochondrial transplantation to fibroblasts counteracts a pro-fibrotic phenotype. <i>International Journal of Molecular Sciences</i>, <i>24</i>(13), 10913.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134502&quot; data-voice=&quot;en-US-BrandonNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134502&amp;voice=en-US-BrandonNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

Rejuvenation Roundup December 2024

Senescent Cells Protect the Bladder: In Aging Cell, a research team has explained why barrier cells in the human bladder are largely senescent and what might lead them to become cancerous. The researchers note that these senescent cells are clearly necessary for proper function of the bladder, suggesting that they should be treated rather than destroyed, such as by improving their mitochondrial function or reducing their oxidative stress. Extending Monkeys’ Reproductive Span With Stem Cells: An

Another Year of Longevity Advocacy and Journalism

<p style="text-align: justify;">The nights are the longest of the year, the holidays are drawing near, and we are back with a festive edition of the Lifespan.io editorial. This time, we bring you some of this year&#8217;s highlights and talk about what the future holds for our content.</p> <h2 style="text-align: justify;"><b>Lifespan.io and SENS Research Foundation merge</b></h2> <p style="text-align: justify;">Regulars will recall that Lifespan Extension Advocacy Foundation and SENS Research Foundation merged in October. We are now the <a href="https://www.lifespan.io/joining-forces-a-shared-mission/">Longevity Research Institute</a> (LRI), an organization focused on rejuvenation biotechnology research and news.</p> <p><img fetchpriority="high" decoding="async" class="aligncenter wp-image-132593" src="https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2.jpg" alt="Lifespan and SENS Merger Announcement Banner" width="1000" height="467" srcset="https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2.jpg 1500w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-400x187.jpg 400w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-745x348.jpg 745w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-256x119.jpg 256w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-300x140.jpg 300w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-1024x478.jpg 1024w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-150x70.jpg 150w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-480x224.jpg 480w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-600x280.jpg 600w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-360x168.jpg 360w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-262x122.jpg 262w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-555x259.jpg 555w, https://www.lifespan.io/wp-content/uploads/2024/09/C38_lifespan_landing_page_banner_revB-2.2_2-1140x532.jpg 1140w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <p style="text-align: justify;">The two organizations have combined to pursue the goal of healthier and longer lives for all. Keith Comito, President of the Board, had this to say about the merge:</p> <p style="text-align: justify;">“Lifespan.io and SRF have shared a rich legacy in the battle against age-related diseases, driven by passion and purpose in both advocacy and research. Today, we unite these powerful forces to forge an organization uniquely equipped to identify and advance the most transformative projects in our field. Together with you, the Lifespan Research Institute will work to create a future where vitality and long-lasting health are within reach for everyone.”</p> <p style="text-align: justify;">Lifespan.io will continue to bring you the latest longevity news from the same website, so there&#8217;s no need to change your bookmarks!</p> <h2 style="text-align: justify;"><b>Celebrating a decade of independent non-profit journalism</b></h2> <p style="text-align: justify;">Lifespan.io has been one of the top sources for non-profit aging research news for the last decade. Here are some of the things we have achieved:</p> <ul style="text-align: justify;"> <li>10 years of independent journalism.</li> <li>270 news articles published this year so far!</li> <li>160 longevity topics and growing.</li> <li>147 leading researchers interviewed since 2014.</li> </ul> <p style="text-align: justify;">Not bad for a small non-profit organization that started with a handful of people, right? We think so, and it has been an awesome experience supporting the aging research field over this last decade.</p> <p style="text-align: justify;">This field is a very unique one, and it is both a challenge and privilege to focus our journalism on it. Since we started 10 years ago, there has been a significant change in the field. This field of research, which a significant part of the public had considered to be fringe, is steadily growing in credibility and respect.</p> <p style="text-align: justify;">Hucksters peddling unscientific nonsense continue to harm our field&#8217;s reputation, but things are starting to improve. In recent years, real science has started to take the spotlight.</p> <p style="text-align: justify;">Many <a href="https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/">rejuvenation treatments are in or near human trials</a>, and the science is gaining traction as its credibility increases. While there is still much work to be done, there is reason for optimism and hope that longer, healthier lives are something that we can achieve in the near future.</p> <h2 style="text-align: justify;"><b>Independent journalism is at risk</b></h2> <p style="text-align: justify;">Dear readers, I am Steve Hill, Editor-in-Chief of Lifespan.io, and I need to tell you about the crisis happening right now in journalism.</p> <p style="text-align: justify;">The anti-competitive practices of big tech firms are an existential threat to independent journalism. Companies like Google and Meta are effectively gatekeepers of online content, deciding what internet users see. While this has long been the case, the level of control they have is now extreme.</p> <p style="text-align: justify;">Facebook, Linkedin, X, and other social media are increasingly trying to keep users on their platforms. They have made social media into a walled garden: a place where external content is consumed without any benefits for its creators, such as independent journalists.</p> <p style="text-align: justify;">The emphasis on paying to be seen on social media, even by your own followers, has gotten completely out of hand. This hurts content creators who are struggling to be seen, doubly so for non-profit organizations like us.</p> <p style="text-align: justify;">Non-profit content makers like us are increasingly being pushed out of internet search results. This is in part thanks to sweeping changes that Google has made to its search algorithm.</p> <p style="text-align: justify;">The risks from AI-generated content are greater than ever before, too. Often, such AI content is filled with misinformation and cannot be a trusted source. On top of that, Google&#8217;s clumsy attempts to stem the tide of low-quality AI content with changes to its search algorithm has damaged many legit content creators too.</p> <p style="text-align: justify;">Finally, the use of AI search overlays means that content creators like us are effectively having our content stolen, repackaged, and served up by Google as their own work. All of this is done without any acknowledgement or reward for content creators&#8217; efforts!</p> <p style="text-align: justify;">All of this means that it’s become harder to reach people and tell them about the amazing work happening in our field. It is absolutely vital, now more than ever before, for independent voices to be heard.</p> <h3 style="text-align: justify;"><b>Why independent longevity journalism is important</b></h3> <p style="text-align: justify;">We are an important voice for the aging and rejuvenation research field. Our <a href="https://www.lifespan.io/ethics-code-of-longevity-journalism/">ethics code of longevity journalism</a> is what makes us stand out from our competitors and makes us a source of information you can trust.</p> <p style="text-align: justify;">Our non-profit status means thaat our news remains free from government and commercial influence and will always be free. This is because we believe in sharing knowledge and a world where science is not locked behind paywalls.</p> <p style="text-align: justify;">But, it’s like the old saying goes: “Use it or lose it!” Put simply, without the support of the community, we cannot continue to be your trusted source for longevity news. If you value independent journalism that isn&#8217;t motivated by profit, please consider supporting us this holiday season!</p> <h3 style="text-align: justify;"><b>How you can support independent longevity journalism</b></h3> <p style="text-align: justify;">If you like what we do and you want to help us to keep doing it, I would like to ask you to support us in one or more ways:</p> <ul style="text-align: justify;"> <li><b>Donate:</b> No matter how big or small, every little bit helps us to keep creating content for you. Help us by <a href="https://www.lifespan.io/eoy-fundraiser-2024/">making a donation</a> today.</li> <li><b>Be a Hero:</b> The most important way you can support our work is by becoming one of our monthly patrons: <a href="https://www.lifespan.io/campaigns/join-us-become-a-lifespan-hero/">the Lifespan Heroes</a>.</li> <li><b>Stay informed:</b> Keep up to speed about what is happening in the exciting world of rejuvenation research by <a href="https://www.lifespan.io/newsletter-sign-up/">joining our monthly newsletter</a>.</li> <li><b>Follow us:</b> We are on <a href="https://www.facebook.com/lifespanio">Facebook</a>, Instagram, <a href="https://linkedin.com/company/5239595">Linkedin</a>, and <a href="https://twitter.com/lifespanio">X</a>.</li> </ul> <p style="text-align: justify;">With your support, independent journalism can continue to thrive, and we can keep bringing you the best in independent journalism covering aging, longevity, and rejuvenation.</p> <p style="text-align: justify;">Best wishes to you and your family for the holidays and a happy new year.</p> <p style="text-align: justify;">Now, on to more positive things as we take a look at this year&#8217;s top stories and future plans for content here on the news outlet.</p> <h2 style="text-align: justify;"><b>Success in the lab for the Longevity Research Institute</b></h2> <p style="text-align: justify;">2024 was a year to celebrate our organization&#8217;s success in the lab. Researchers at the Longevity Research Institute (LRI) published results in December showing they had achieved the <a href="https://www.lifespan.io/news/nuclear-expression-of-a-mitochondrial-gene-in-mice/">expression of an essential mitochondrial gene in the nucleus</a> and proper functioning of the protein.</p> <p><img decoding="async" class="aligncenter size-full wp-image-134188" src="https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing.jpg" alt="Gene editing" width="1000" height="562" srcset="https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing.jpg 1000w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-400x225.jpg 400w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-705x396.jpg 705w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-256x144.jpg 256w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-300x169.jpg 300w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-150x84.jpg 150w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-480x270.jpg 480w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-600x337.jpg 600w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-360x202.jpg 360w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-262x147.jpg 262w, https://www.lifespan.io/wp-content/uploads/2024/12/Gene-editing-555x312.jpg 555w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <p style="text-align: justify;">This important research builds on years of work towards finding a solution to age-related mitochondrial dysfunction. The mitochondria are the power stations of our cells. Unfortunately, as we age, they get increasingly damaged and unable to function.</p> <p style="text-align: justify;">To combat this, LRI aims to make copies of the mitochondrial genes inside the safety of the cell nucleus. This research brings us another step closer to that final goal. If we can keep our mitochondria healthy and functional as we age, it could have big implications for our health and longevity.</p> <p style="text-align: justify;">“This work represents the culmination of more than a decade’s worth of effort to provide a genetic backup system for mitochondrial DNA in mammals, for which inherited mutations cause disease in nearly 1 in 200 people,” said Dr. E. Lillian Fishman, Director of Research and Education at LRI.</p> <p style="text-align: justify;">This line of research could help combat diseases such as age-related muscle loss, Parkinson’s, and Alzheimer’s. It might also be used to potentially treat mitochondrial diseases that cause seizures and blindness.</p> <h2 style="text-align: justify;"><b>Top stories of 2024</b></h2> <p style="text-align: justify;">It’s been a busy year packed with great stories, but as is customary for this time of year, here are some of the best ones from 2024.</p> <p style="text-align: justify;"><img decoding="async" class="aligncenter size-full wp-image-131664" src="https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die.png" alt="Bryan Johnson Don't Die" width="1000" height="562" srcset="https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die.png 1000w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-400x225.png 400w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-705x396.png 705w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-256x144.png 256w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-300x169.png 300w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-150x84.png 150w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-480x270.png 480w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-600x337.png 600w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-360x202.png 360w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-262x147.png 262w, https://www.lifespan.io/wp-content/uploads/2024/09/Bryan-Johnson-Dont-Die-555x312.png 555w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <h3 style="text-align: justify;"><b>I Dined with Bryan Johnson and Didn’t Die</b></h3> <p style="text-align: justify;">Journalist Arkadi Mazin was invited to Bryan Johnson’s home for one of his famous “<a href="https://www.lifespan.io/news/i-dined-with-bryan-johnson-and-didnt-die/">Don’t Die Dinners</a>”.</p> <p style="text-align: justify;">Johnson has been hosting these dinners for a few years. His guests often include celebrities and key figures in longevity research and important figures in the longevity research field.</p> <p style="text-align: justify;">Johnson is a somewhat controversial figure in the longevity community. His efforts to improve his health and extend his life have sparked much discussion. In this interview, Arkadi delves into what drives him to do the things he does for longevity.</p> <p style="text-align: justify;">Whether his approach is right or wrong is a subjective opinion, and you may or may not agree with his methods. However, we believe you will enjoy this interview either way.</p> <p style="text-align: center;"><img loading="lazy" decoding="async" class="aligncenter size-full wp-image-133002" src="https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350.jpg" alt="An hourglass showing time is running out." width="1000" height="566" srcset="https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350.jpg 1000w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-400x226.jpg 400w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-700x396.jpg 700w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-256x145.jpg 256w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-300x170.jpg 300w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-150x85.jpg 150w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-480x272.jpg 480w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-600x340.jpg 600w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-360x204.jpg 360w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-262x148.jpg 262w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-555x314.jpg 555w, https://www.lifespan.io/wp-content/uploads/2024/10/shutterstock_2260451915-e1729175573350-768x435.jpg 768w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <h3 style="text-align: justify;"><b>Have We Maxed Out on Life Expectancy Gains?</b></h3> <p style="text-align: justify;">One research paper that seems to have ruffled quite a few feathers in the community suggested that <a href="https://www.lifespan.io/news/have-we-maxed-out-on-life-expectancy-gains/">radical life extension was all but impossible in this century</a>.</p> <p style="text-align: justify;">Often, predictions like these are followed by a demonstration that the said impossible thing is in fact possible. The Wright Brothers are an example of that: they demonstrated that heavier-than-air flight was perfectly possible despite experts at the time saying it was not.</p> <p style="text-align: justify;">However, what seems to have escaped quite a few people about this paper was that Jay Olshanky and the other authors did not discount the possibility that radical life extension may be achieved if breakthroughs in rejuvenation biotechnology were to occur.</p> <p style="text-align: justify;">It really is the case that nature is not going to solve aging and that life expectancies are no longer rising as they have in previous decades. It says everything about what nature will do, but puts no limits on what we might achieve through science.</p> <p><img loading="lazy" decoding="async" class="aligncenter size-full wp-image-134119" src="https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview.jpg" alt="Mehmood Khan Interview" width="1000" height="562" srcset="https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview.jpg 1000w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-400x225.jpg 400w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-705x396.jpg 705w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-256x144.jpg 256w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-300x169.jpg 300w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-150x84.jpg 150w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-480x270.jpg 480w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-600x337.jpg 600w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-360x202.jpg 360w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-262x147.jpg 262w, https://www.lifespan.io/wp-content/uploads/2024/12/Memhood_Khan_Interview-555x312.jpg 555w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <h3 style="text-align: justify;"><b>Mehmood Khan on Aging Policy and Collaboration</b></h3> <p style="text-align: justify;">Recently, Arkadi did an <a href="https://www.lifespan.io/news/mehmood-khan-on-aging-policy-and-collaboration/">interview with Dr. Mehmood Khan</a> about aging policy and how reframing the goal of rejuvenation biotechnology might help to drive progress forward faster. Longevity apparently means something quite different to high-level policy makers than it might for most people.</p> <p style="text-align: justify;">To these policymakers, it isn’t about people living longer for the sake of living longer but about productivity. This is why we need people like Khan advocating for our field and being able to speak the language policymakers want to hear to unlock funding for longevity research.</p> <p style="text-align: justify;">As sad as it is that we need to argue for the right to live longer and healthier lives through science, this is the reality of things. We think this interview might be an interesting read and help you understand what we are up against when it comes to advocacy and making policy work for us, not against us.</p> <p style="text-align: center;"><img loading="lazy" decoding="async" class="aligncenter size-full wp-image-133261" src="https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare.jpg" alt="AI in Healthcare" width="1000" height="562" srcset="https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare.jpg 1000w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-400x225.jpg 400w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-705x396.jpg 705w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-256x144.jpg 256w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-300x169.jpg 300w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-150x84.jpg 150w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-480x270.jpg 480w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-600x337.jpg 600w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-360x202.jpg 360w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-262x147.jpg 262w, https://www.lifespan.io/wp-content/uploads/2024/11/AI-in-Healthcare-555x312.jpg 555w" sizes="(max-width: 1000px) 100vw, 1000px" /></p> <h3 style="text-align: justify;"><b>AI in Longevity: The Reality Today</b></h3> <p style="text-align: justify;">Lifespan.io journalist Maria Isabella brought us an overview of the role of <a href="https://www.lifespan.io/news/ai-in-longevity-the-reality-today/">AI in longevity research</a> and how it is being used in healthcare today.</p> <p style="text-align: justify;">Patient data analysis is a currently popular use case for AI, and a number of companies are involved in this. AI isn&#8217;t without its potential issues though, and we take a look at some of these in this article.</p> <p style="text-align: justify;">We are planning to delve deeper into the emerging use of AI in relation to aging and rejuvenation research in the future, but for now, we think you should enjoy this high-level summary of the technology.</p> <p style="text-align: center;"><img loading="lazy" decoding="async" class="aligncenter size-full wp-image-131231" src="https://www.lifespan.io/wp-content/uploads/2024/08/Diamandis_Tekengebied_1-e1724091250805.png" alt="Peter Diamandis is a major influence on the field of aging and rejuvenation research." width="1000" height="562" /></p> <h3 style="text-align: justify;"><b>Peter Diamandis: “Stay Healthy, Anti-Aging Tech is Coming”</b></h3> <p style="text-align: justify;">In August, <a href="https://www.lifespan.io/news/peter-diamandis-interview-longevity/">Peter Diamandis shared his thoughts on the aging and rejuvenation field</a> with Arkadi.</p> <p style="text-align: justify;">Diamandis is an influential figure in the aging and rejuvenation world. He is an entrepreneur and investor in several fields, including commercial space flight and rejuvenation biotechnology.</p> <p style="text-align: justify;">During this fascinating interview, he shares his insights into how to encourage high-net-worth investors to get into the longevity space and why it is such a challenge to do so.</p> <p style="text-align: justify;">While there are a number of challenges our field faces in both progressing the research and funding for that research, Diamandis offers an overall message of hope and positivity for the future that we think you will enjoy.</p> <p style="text-align: justify;">These are just some of the great articles Lifespan.io has published this year, and we hope you continue to enjoy reading more in 2025.</p> <h2 style="text-align: justify;"><b>Future improvements to our content</b></h2> <p style="text-align: justify;">Our commitment to bring you the best in independent journalism will continue in 2025. In fact, we are scaling up what we plan to offer in the new year in order to bring you even more quality content.</p> <p style="text-align: justify;">Earlier this year, we did an audience survey, and the results were amazing! We asked you what you wanted to see us focusing on, you told us, and we listened. So, for 2025, we are going to be exploring new and exciting content and bringing you more of the things you asked for.</p> <ul style="text-align: justify;"> <li>Based on your feedback, we are going to be publishing more interviews, op-eds (opinion pieces by leading external researchers), special reports, feature pieces, and more! <ul style="text-align: justify;"> <li><b>The ethics of launching a supplement based on your research (op-ed) </b>&#8211; We&#8217;ll invite a leading expert to speak about the perils and positives of researchers who opt to launch supplements following their initial research. Is it ethical or harmful to perception and progress in the field?</li> <li><b>The hype and reality of the field (op-ed)</b> &#8211; While we should be committed to the defeat of aging, it is important to ensure we remain grounded and realistic. A leading expert (probably Matt K) will discuss the field in a sober and realistic manne<b>r.</b></li> <li><b>The reality of AI in research (op-ed)</b> &#8211; We&#8217;ll invite a leading expert to talk about how exactly AI is being used in the research setting, its potential, and its limitations. There is a lot of misconception around what AI is likely to achieve in the context of aging research, so it&#8217;s important to have a grounded discussion about it.</li> <li><b>Reviewing progress in the field (review)</b> &#8211; We&#8217;ll publish a high-level report on where we are in the context of achieving damage repair. We used to do a yearly report called “SENS &#8211; Where are we now?” This will be similar but with a wider Hallmarks of Aging focus to match our excellent Rejuvenation Roadmap.</li> </ul> </li> <li>We will be exploring the world of longevity investment and business and taking deep dives into the things investors want to know about the field: <ul> <li><b>Lifespan prediction </b>&#8211; We&#8217;ll look at capabilities of AI in this area, companies working in this field, actual technology, and why finance companies may be interested (spoiler: it’s medical and pension costs).</li> <li><b>AI and Longevity </b>&#8211; We&#8217;ll take a look at the reality of solutions and perspectives, including external expert commentary.</li> <li><b>DeSci and longevity</b> &#8211; How much funding has DeSci/crypto really generated? We&#8217;ll analyze the impact of DeSci on the field and asking the question: Has DeSci been a success or failure in driving progress? We&#8217;ll look at the biggest funding of the year, research, what has been learned, and what could be ahead in 2025 for DeSci.</li> <li><b>Thinking of doing research?</b> &#8211; We&#8217;ll discuss funding, including crypto, along with the reality of application procedures, including commentary from internal and external experts.</li> <li><b>Economics of living longer</b> &#8211; Are we ready? We&#8217;ll discuss infrastructure, finance, health and planning.</li> </ul> </li> <li><strong>Expanding the Rejuvenation Roadmap</strong> &#8211;  We aim to continue to grow the Rejuvenation Roadmap. We are currently tracking 224 rejuvenation biotech interventions and biomarkers, and we want to increase that to 300+ in the next year.</li> </ul> <p style="text-align: justify;">There is plenty to look forward to in the new year, and we hope you will continue to visit us for your aging research news. Finally, we wish you Happy Holidays from the Lifespan.io team!</p> <h3 style="text-align: justify;"><b>Stay up to date, join the newsletter!</b></h3> <p style="text-align: justify;">If you want to keep up with the latest research news, then feel free to <a href="https://www.lifespan.io/newsletter-sign-up/">join our newsletter</a>. We will see you in the next editorial with more updates and news on what our new organization has been doing to defeat age-related diseases.</p> <div id="playht-shortcode" data-shortcode=" &lt;div id=&quot;playht-iframe-wrapper&quot; style=&quot;display:flex; max-height:&quot;90px&quot;; justify-content:center&quot;&gt; &lt;iframe allowfullscreen=&quot;&quot; frameborder=&quot;0&quot; scrolling=&quot;no&quot; class=&quot;playht-iframe-player&quot; data-appId=&quot;E9FaMfn-qe&quot; article-url=&quot;https://www.lifespan.io/?p=134468&quot; data-voice=&quot;en-US-BrandonNeural&quot; src=&quot;https://play.ht/embed/?article_url=https://www.lifespan.io/?p=134468&amp;voice=en-US-BrandonNeural&amp;config={&quot;width&quot;:&quot;&quot;100%&quot;&quot;,&quot;height&quot;:&quot;&quot;90px&quot;&quot;,&quot;alignment&quot;:&quot;center&quot;,&quot;title&quot;:&quot;Audio&quot;,&quot;message&quot;:&quot;Hello&quot;,&quot;download_text_button&quot;:&quot;Download&quot;}&quot; width=&quot;&quot;100%&quot;&quot; height=&quot;&quot;90px&quot;&quot; style=&quot;max-height:&quot;90px&quot;&quot;&gt; &lt;/iframe&gt; &lt;/div&gt;"></div>

The Best Talks From Longevity Summit 2024

After those senescent cells start producing inflammatory factors, neutrophils arrive at the scene to mark the senescent cells for destruction. However, with age, this immune-mediated elimination of senescent cells becomes compromised. “We spent years identifying susceptibility nodes in senescent blood vessel cells and landed on a protein called BCL-XL, which lives inside mitochondria and sequesters death effectors,” Sapieha said.. The scientists decided to go specifically after senescent endothe

Why Research Teams Should Email XPRIZE Healthspan Now

We were going through team submissions and metadata, and she just started giggling and said, &#8220;Jamie, it&#8217;s working.&#8221; We&#8217;re just at the start &#8211; there&#8217;s so much left to do in the next six years &#8211; but that we could at least get to this stage speaks volumes. We received some information after this interview was completed:. XPRIZE Healthspan closes primary registration on Friday, 20 December 2024, but we are extending the deadline for Qualifying Submission upl

Delivering longevity medicine in a primary care setting

Singapore clinic ‘experiment’ demonstrates a potential path towards democratization of longevity medicine. Nestled in the densely populated streets of Singapore, a longevity clinic with a difference is quietly conducting its work. At a glance, Bartley Clinic appears to offer many of the diagnostic and prevention services offered by high-end, concierge clinics around the world, but it’s doing so in a primary care setting. The brainchild of Dr Hisham Badaruddin, Bartley Clinic is a general

The Best Talks of GSA 2024

<div><p style="text-align: justify;">Today, we bring you a selection of presentations from the <a href="https://www.gsa2024.org/">annual conference organized by the Gerontological Society of America</a>.</p> <p style="text-align: justify;">Most of our savvy readers, if asked to name the biggest gerontology conference, would probably go with the venerable <a href="https://www.lifespan.io/news/for-the-11th-year-in-copenhagen-highlights-from-ardd-2024/">ARDD in Copenhagen</a> or the new favorite, Hevolution Foundation’s Healthspan Summit in Riyadh. Yet, both pale in comparison with the enormous conference (still not the biggest in the world though) organized annually by the Gerontological Society of America. GSA 2024 was held in my hometown of Seattle earlier this month, and I was there to witness all the grandeur.</p> <p style="text-align: justify;">And big it was! There were 4,000 participants over four days (five if you count the pre-conference workshops), and it occupied the entire four floors of the Seattle Convention Center. However, the lion’s share of the conference was focused not on the biology of aging or longevity biotech companies but rather on caring for the elderly and the societal aspects of aging. We in the longevity field tend to forget about this immense industry of helping people during their last decades of life and the legions of dedicated people who provide this help.</p> <p style="text-align: justify;">In sharp contrast, the biology of aging track at the conference was tiny, with a couple of dozen people struggling to fill the modestly sized auditorium. Nevertheless, it featured high-quality talks and some of the biggest names in the longevity field, such as Harvard Professor <a href="https://www.lifespan.io/news/david-sinclair-hopes-rejuvenation-possible-in-a-few-decades/">David Sinclair</a>. Sinclair’s talk was a part of the pre-conference workshop on the hallmarks of aging, which makes it a great starting point for this selection of talks.</p> <h2 style="text-align: justify;"><b>Cellular reprogramming is moving closer to the clinic</b></h2> <p style="text-align: justify;">Fame and controversy notwithstanding, Sinclair remains one of the leading and most productive geroscientists, conducting cutting-edge research out of his Harvard lab and overseeing a few companies. In his talk, he provided an overview of his <a href="https://www.lifespan.io/news/sinclair-epigenetic-information-theory/">information theory of aging</a> and the recent research by his team, which we have <a href="https://www.lifespan.io/news/reversing-cellular-age-in-mice-restores-vision/">previously featured</a> on our site.</p> <p style="text-align: justify;">Information, Sinclair said, is becoming ever more relevant to understanding aging. All the hallmarks of aging “talk to each other.” However, with time, this biological information becomes corrupted by “noise,” which is introduced in several ways, including via DNA mutations and unwanted changes in gene expression (epimutations).</p> <p style="text-align: justify;">Mutations and epimutations are inextricably linked by the fact that certain proteins (namely, some of the members of the sirtuin family) participate both in regulating gene expression by repressing chromatin and in repairing DNA breaks. When those proteins are summoned to a DNA break, they abandon their posts as chromatin guardians and do not always successfully return.</p> <p style="text-align: justify;">Sinclair’s lab has created a mouse model involving induced changes to the epigenome (ICE) into which the researchers can induce a modest amount of DNA breaks, which are faithfully repaired, thus not leading to mutations – however, the repair process leads to epimutations. This allowed the team to uncouple genetic and epigenetic changes and look at how the latter affect aging. According to Sinclair, experiments with ICE mice have confirmed that epigenetic changes induce aging across multiple hallmarks, even in the absence of DNA mutations.</p> <p style="text-align: justify;">Sinclair’s idea is that the information required to restore the epigenome to its original or at least younger state, which happens during cellular reprogramming, must be stored somewhere in the cell; therefore, every epigenetic change is “recorded” by yet unknown molecular mechanisms. Sinclair believes his group might have taken the first steps in identifying these mechanisms: they showed that the enzymes SIRT1 and TET2, which are involved in epigenetic alterations, bind to the same sites in certain genes as the Yamanaka reprogramming factors.</p> <p style="text-align: justify;">Another direction that Sinclair pursues is cellular reprogramming’s clinical applications. His team has developed a protocol that uses three of the four classic Yamanaka factors (OCT4, SOX2, and KLF4, or “OSK”), deliberately omitting c-Myc, which is an oncogene. In addition to improving safety, this allows for continuous expression of the reprogramming factors without throwing the cells back into pluripotency. For more details, read <a href="https://www.lifespan.io/news/life-biosciences-is-bringing-reprogramming-to-the-clinic/">our recent interview</a> with Sharon Rosenzweig-Lipson, CSO of Life Biosciences, one of Sinclair’s companies.</p> <p style="text-align: justify;">Life builds on Sinclair’s work in restoring vision via cellular reprogramming. In his talk, Sinclair showed a video of a formerly blind aged mouse responding to visual stimuli after just three weeks of OSK treatment. Experiments have also been performed on rats and non-human primates. Life Biosciences might be very close to bringing cellular reprogramming to the clinic, as Sinclair announced human trials scheduled for August 2025.</p> <p style="text-align: justify;">While gene therapy with these factors would be expensive, the Sinclair lab is developing more affordable alternatives. The researchers have identified cocktails of small molecules that can induce partial cellular reprogramming.</p> <p style="text-align: justify;">The research has progressed from cells to miniature tissue models (organoids). The researchers’ work with cellular senescence has delivered particularly promising results, with senescent cells showing dramatic improvements after just ten days of treatment.</p> <p style="text-align: justify;">While the initial focus is on eye diseases such as glaucoma and AMD (age-related macular degeneration, a very hard disease to tackle), Sinclair hopes that their findings “might be relevant to a whole variety of diseases, not just the eye.”</p> <h2 style="text-align: justify;"><b>From toast to aging: the hidden impact of glycation</b></h2> <p style="text-align: justify;">For most of his career, Prof. Pankaj Kapahi of the Buck Institute on Aging has been studying glycation, a non-enzymatic chemical reaction where sugar molecules, such as glucose, bond to proteins, lipids, or DNA. Glycation is also the chemical process that makes toast brown and flavorful (“We’re slowly toasting away,” Kapahi joked).</p> <p style="text-align: justify;">Glycation impairs molecules’ normal function and is known to contribute to aging and diseases like diabetes and Alzheimer’s. Advanced glycation end-products are abbreviated as AGEs.</p> <p style="text-align: justify;">Kapahi’s recent research focuses on methylglyoxal (MGO), a highly reactive molecule produced whenever cells use glucose and a precursor to AGEs. “It’s about 1,000 times more reactive than glucose,” Kapahi explained. “It has both aldehyde and ketone groups that can bind DNA, proteins, and lipids through covalent bonds, and there’s no escape from its production.”</p> <p style="text-align: justify;">This reactivity affects multiple hallmarks of aging, including mitochondrial function and epigenetic state. The researchers discovered that it also drives cellular senescence. Things are complicated by the fact that MGO might not be just a harmful byproduct but also have regulatory roles, including appetite regulation and glycolysis control.</p> <p style="text-align: justify;">“Our current research shows glycation accelerates aging in multiple organs: heart, eye, fat cells, brain (by affecting myelination), and pancreas,” Kapahi said. “It also increases senescence markers in fat and affects glucose homeostasis.”</p> <p style="text-align: justify;">The team screened about 600 compounds to find AGE-lowering agents. Bictinamide emerged as a promising candidate, and the team has developed a five-compound cocktail. It includes lipoic acid, which effectively reduces the burden of methylglyoxal and AGE across tissues.</p> <p style="text-align: justify;">This cocktail, called Gly-Low, improves aortic stiffening, glucose tolerance even in normal mice, and neuromuscular balance. Impressively, it extends lifespan in mice when administered late in life (around 24 months). In high-fat diet models, it reduces blood glucose and improves glucose tolerance while significantly reducing inflammatory cytokine loads.</p> <p style="text-align: justify;">The researchers are now investigating the mechanisms behind these effects. “We’re using click chemistry to identify methylglyoxal-modified proteins,” Kapahi explained, “hypothesizing that these modifications might make proteins appear foreign to the immune system, triggering inflammatory responses. This work should help us understand how glycation drives aging and age-related diseases.”</p> <h2 style="text-align: justify;"><b>When life gives you fibroblasts, make neurons!</b></h2> <p style="text-align: justify;">Larissa Traxler from Jerome Mertens’s Lab at UC San Diego gave a talk titled “From Old Skin to Old Neurons: Direct Conversion to Explore the Interface between Cellular Aging and Disease.”</p> <p style="text-align: justify;">One of the reasons we lack cures for diseases like Alzheimer’s, she said, is because aging, a major risk factor, is so heterogeneous. No unifying etiology for Alzheimer’s exists, and almost all cases are sporadic. This inspired Traxler’s team to develop individual-specific analysis approaches that can capture this heterogeneity, which they achieve by using direct cellular reprogramming of patient-derived fibroblasts into neurons.</p> <p style="text-align: justify;">Starting from patient skin biopsies, they then use lentiviral factors to induce direct conversion with 40-50% efficiency. After cell sorting, more than 95% purity is achieved. The resulting induced neurons (iNs) are a combination of excitatory and inhibitory types and are mostly similar to frontal cortex neurons. Using various combinations of transcription factors such as Ngn2 and Ascl1, the team can generate different neuronal subtypes.</p> <p style="text-align: justify;">A crucial aspect of the system is that these iNs maintain the biological age of the donor and their specific aging signature. “This is fundamentally different from iPSC-derived neurons, which reset to pre-birth ages according to methylation clocks,” Traxler said. “Our iNs reflect individual donor ages and display adult-stage characteristics, while iPSC neurons resemble fetal stages.”</p> <p><img fetchpriority="high" decoding="async" class="aligncenter wp-image-134074 size-full" src="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1.png" alt="GSA2024 1" width="1000" height="558" srcset="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1.png 1000w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-400x223.png 400w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-710x396.png 710w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-256x143.png 256w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-300x167.png 300w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-150x84.png 150w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-480x268.png 480w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-600x335.png 600w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-360x201.png 360w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-262x146.png 262w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-1-555x310.png 555w" sizes="(max-width: 1000px) 100vw, 1000px"></p> <p style="text-align: justify;">This age retention is particularly visible in adult neuronal splicing, such as in MAPT (Tau) genes, where the researchers observe adult-specific combinations of isoforms and their phosphorylation. Interestingly, humans have much more alternative splicing than mice, a feature that cannot be properly modeled in mouse systems (mouse models of Alzheimer’s have indeed been unreliable, and their relevance to human Alzheimer’s is questioned).</p> <p style="text-align: justify;">The group went even further, having developed multicellular constructs that combine iNs with glial cells on polymer scaffolds. These form dense three-dimensional structures with synaptic connections. In these 3D constructs, the researchers have observed amyloid deposition with clear differences between familial and sporadic AD cases.</p> <p style="text-align: justify;">Interestingly, <a href="https://www.lifespan.io/news/study-of-direct-reprogramming-challenges-consensus/">we recently reported</a> on a study claiming that low efficiency of direct fibroblast-to-neuron reprogramming happens because only a small subset of stemlike cells (neuron crest progenitor cells) embedded within differentiated skin cells can produce neurons. However, the much higher efficiency cited by Traxler seems to contradict this claim. It is possible that her team uses a stronger reprogramming protocol that can cause a wider variety of skin cells to transition into neurons.</p> <h2 style="text-align: justify;"><b>Can this diabetes drug extend lifespan?</b></h2> <p style="text-align: justify;">Carolina Solis-Herrera from the University of Texas spoke at a session focused on repurposing existing drugs for slowing aging. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed as glucose-lowering medications for type 2 diabetes, have attracted considerable attention in the longevity field after evidence appeared that this class of drugs positively affects both lifespan and healthspan. In particular, canagliflozin <a href="https://www.lifespan.io/news/estrogen-metabolite-robustly-increases-lifespan-in-male-mice/">was among the handful of drugs</a> that produced significant life extensions in mice in the rigorous Interventions Testing Program (ITP) trials.</p> <p style="text-align: justify;">Solis-Herrera’s group is trying to unravel the mechanisms of action behind those benefits. Recent evidence from trials shows that patients on SGLT2 inhibitors, both with and without diabetes, experienced fewer cardiovascular events, reduced hospitalization for heart failure, and improved kidney function. Cardiovascular and renal problems are, of course, two major causes of death in both diabetic and non-diabetic people.</p> <p style="text-align: justify;">“The cardiovascular protection we see with SGLT2 inhibitors emerges remarkably quickly – between six to eight weeks, far too fast to be explained by traditional risk factor improvements,” Solis-Herrera said. “This suggests there must be other mechanisms at work.”</p> <p style="text-align: justify;">Results show that SGLT2 inhibitors work along several pathways. They enhance the clearance of senescent cells; induce calorie loss by promoting urinary glucose excretion, which resembles caloric restriction; modulate key nutrient-sensing pathways involved in aging, such as mTOR and AMPK; and reduce age-related low-grade inflammation (inflammaging) and oxidative stress.</p> <p style="text-align: justify;">The researchers currently focus on the “ketone hypothesis”: that SGLT2 inhibitors increase the production of ketone bodies, such as beta-hydroxybutyrate (BHB). “We found that ketones reduce oxygen consumption and increase efficiency in various organs, including heart and kidneys,” Solis-Herrera said. “We’re now investigating applications in Alzheimer’s, diabetic retinopathy, dementia, and post-transplant patients for reducing rejection – that’s why we call SGLT2 inhibitors “the gift that keeps giving.”</p> <p><img decoding="async" class="aligncenter size-full wp-image-134075" src="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2.png" alt="GSA2024 2" width="1000" height="578" srcset="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2.png 1000w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-400x231.png 400w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-685x396.png 685w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-256x148.png 256w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-300x173.png 300w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-150x87.png 150w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-480x277.png 480w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-600x347.png 600w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-360x208.png 360w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-262x151.png 262w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-2-555x321.png 555w" sizes="(max-width: 1000px) 100vw, 1000px"></p> <p style="text-align: justify;">Solis-Herrera reported on a new study in humans, where patients on SGLT2 inhibitors showed decreased inflammatory biomarkers, including TNF-alpha; a decrease in oxidation markers and senescent cell burden; and a significant decrease in visceral fat across multiple organs. “In summary,” she concluded, “SGLT2 inhibitors, originally created for diabetes, have emerged as potentially powerful anti-aging compounds. Their mechanisms likely involve a metabolic shift from glucose excretion to ketogenesis, which appears to be beneficial rather than maladaptive. They modulate key molecular pathways like mTOR and AMPK, reducing inflammation and oxidation.”</p> <h2 style="text-align: justify;"><b>Looking beyond weight loss</b></h2> <p style="text-align: justify;">John Newman, another representative of Buck Institute on Aging at the conference, talked about an even more hyped type of drug: glucagon-like peptide (GLP-1) receptor agonists, such as semaglutide, the principal ingredient of Ozempic and Wegovy. These drugs have revolutionized the treatment of diabetes and obesity, but many researchers believe they provide anti-aging benefits outside this context. Newman said he was very enthusiastic about GLP-1 agonists, but “there are critical gaps that need filling before we let that enthusiasm run away.”</p> <p style="text-align: justify;">Newman explained that GLP-1, a small peptide hormone secreted by L cells in the gut epithelium and circulating throughout the body, reduces motility in the gut and slows glucose absorption. In the pancreas, it enhances glucose-stimulated insulin secretion to reduce hyperglycemia. However, endogenous GLP-1 is rapidly degraded, with a half-life in plasma “in the order of minutes.”</p> <p style="text-align: justify;">The GLP-1 receptor also interacts intracellularly with various aging-related pathways, such as mTOR and FOXO, enhancing mitochondrial function and dampening inflammation. “All these pathways,” Newman said, “are very familiar to geroscientists, and this integration of GLP-1 receptor signaling with mechanisms of aging is part of why the idea of GLP-1 receptor agonists as gerotherapeutics is so tempting.”</p> <p><img decoding="async" class="aligncenter size-full wp-image-134076" src="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3.png" alt="GSA2024 3" width="1000" height="552" srcset="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3.png 1000w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-400x221.png 400w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-717x396.png 717w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-256x141.png 256w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-300x166.png 300w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-150x83.png 150w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-480x265.png 480w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-600x331.png 600w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-360x199.png 360w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-262x145.png 262w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-3-555x306.png 555w" sizes="(max-width: 1000px) 100vw, 1000px"></p> <p style="text-align: justify;">The GLP-1 receptor is widely distributed in the body, including in hypothalamic neurons, which is how it regulates satiety and appetite. It is also present in the heart, which might explain the cardiovascular benefits.</p> <p style="text-align: justify;">Large-scale trials have shown a significant decrease in cardiovascular mortality in obese and/or diabetic patients. However, gastrointestinal side effects are a major problem: virtually all patients on GLP-1 receptor agonists will eventually experience them, and they are severe enough to cause a 5%-8% dropout in studies.</p> <p style="text-align: justify;">“The results are striking for diabetes treatment and, within either diabetes or obesity, for atherosclerotic disease, kidney disease, and heart failure with preserved ejection fraction,” Newman said. “But does this make them gerotherapeutics? Not necessarily – it makes them highly effective diabetes and obesity treatments.”</p> <p style="text-align: justify;">For us to decide that these drugs are indeed geroprotectors, he explained, we have to see efficacy in diseases outside this metabolic cluster, such as neurodegenerative disease, cancer, and osteoporosis. Small trials in Parkinson’s and Alzheimer’s diseases showed some promise, but the results were not dramatic. A large Alzheimer’s trial (EVOKE) is ongoing. Importantly, this is one of the first large trials in non-obese people.</p> <p style="text-align: justify;">“The big picture,” Newman summarized, “is that while these are very effective agents in obesity and diabetes, we don’t know if benefits extend beyond these conditions or if cardiovascular and kidney protection is independent of weight loss – crucial questions for their potential as gerotherapeutics. Questions remain about the effects on sarcopenic obesity and diseases of aging not caused by obesity or diabetes. Much work remains to be done.”</p> <h2 style="text-align: justify;"><b>Cellular reprogramming for organ transplantation</b></h2> <p style="text-align: justify;">Pradeep Reddy of Juan Carlos Izpisua Belmonte’s lab gave a fascinating talk on cellular reprogramming. Belmonte is one of the pioneers of partial reprogramming and the first to demonstrate significant life extension in progeroid mice. Like several other first-tier geroscientists, Belmonte, previously at Salk Institute, was recruited by Altos Labs. Reddy’s talk presented a rare opportunity to gauge how things are going at the best-funded longevity startup in the world.</p> <p style="text-align: justify;">Reddy started by bringing up the lab’s work from several years ago on Hutchinson-Gilford progeria syndrome (HGPS). When the researchers reprogrammed fibroblasts from HGPS patients to induced pluripotent stem cells (iPSCs), “one striking observation was that all the aging hallmarks their cells initially showed were totally reversed, even though the mutation was still present,” Reddy said.</p> <p style="text-align: justify;">When these iPSCs were re-differentiated back to somatic lineages, they started to manifest the disease phenotype again. However, the team realized the importance of the first part: “that it’s possible to take a pre-diseased cell and reset or reverse those disease markers.”</p> <p style="text-align: justify;">Previously, partial reprogramming was mostly discussed in the context of aging. However, their results led the team to look for opportunities to apply reprogramming to contexts other than aging, “changing the trajectory of cells from diseased to healthy.”</p> <p style="text-align: justify;">“We conducted several studies in aged animals across different tissues,” Reddy said. “It’s not specific to only certain cell types – it can be a broad, agnostic approach. One thing that happens during loss of chromatin stability in disease or aging is loss of cell identity, which leads to decreased functional fidelity.”</p> <p style="text-align: justify;">One epigenetic alteration that is ubiquitous and important in aging is the epithelial-to-mesenchymal transition (EMT), in which epithelial cells lose cellular adhesion and become more motile. EMT can play a beneficial role in wound healing, but it also harms the original function of epithelial cells and is one of the central mechanisms of invasion and metastasizing in cancer.</p> <p style="text-align: justify;">The researchers observed increased EMT signatures in models of liver disease. “Similarly, we see the same phenotype in different cardiomyopathies, lung, and kidney disease,” Reddy said. “It’s a common phenotype, not specific to one tissue.” Partial reprogramming led to the erasure of these mesenchymal signatures in a matter of two to four days, which can explain early benefits.</p> <p style="text-align: justify;">One area where the researchers attempted to apply partial reprogramming is cellular senescence since senescence cells undergo drastic epigenetic changes. They saw decreased levels of SASP (senescence-associated secretory phenotype) elements such as p16, increased resilience, less hair graying, and improved wound healing in treated mice.</p> <p style="text-align: justify;">Delivering reprogramming factors via viral vectors remains a challenge since, with systemic delivery, most particles end up in the liver. Reddy’s team sought to rejuvenate kidneys, but the delivery problem seemed insurmountable until they decided to take a page from clinical practices, where donor organs are often connected to perfusion machines ex vivo for up to several hours to keep them viable. The idea was to add reprogramming factors to the perfusion solution in order to increase the organ’s fitness.</p> <p style="text-align: justify;">In collaboration with a clinic in Barcelona, the researchers worked on kidney transplantation in rats. As expected, organs from old donors were less viable, but reprogramming during perfusion showed promising results.</p> <p><img loading="lazy" decoding="async" class="aligncenter size-full wp-image-134077" src="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4.png" alt="GSA2024 4" width="1000" height="540" srcset="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4.png 1000w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-400x216.png 400w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-733x396.png 733w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-256x138.png 256w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-300x162.png 300w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-150x81.png 150w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-480x259.png 480w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-600x324.png 600w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-360x194.png 360w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-262x141.png 262w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-4-555x300.png 555w" sizes="(max-width: 1000px) 100vw, 1000px"></p> <p style="text-align: justify;">“This platform could help expand the donor pool by allowing us to improve suboptimal organs that would otherwise be discarded,” Reddy said. “We’ve built a modified perfusion system that doesn’t require complete transplantation – organs can remain connected to the body while undergoing perfusion, making it more applicable for age-related disease cases.”</p> <h2 style="text-align: justify;"><b>No limit for New Limit</b></h2> <p style="text-align: justify;">Not as hyped as Altos Labs, New Limit is nevertheless another exciting company working in the field of cellular reprogramming. Jacob Kimmel, who co-founded the company after stints at UCSF and Alphabet’s anti-aging company Calico, gave a captivating overview of its research.</p> <p style="text-align: justify;">New Limit is built on the premise that the classic Yamanaka reprogramming factors (OSKM) are not special, and many other rejuvenating factors and combinations can be found, tailored to specific cell types and contexts. “We plan to formulate these combinations into medicines using mRNA technology, similar to what many of us experienced with COVID vaccines,” Kimmel said. “Finally, we want to deploy these clinically to treat pathologies that will eventually affect all of us.”</p> <p style="text-align: justify;">While New Limit is working on several cell types and indications, in this talk, Kimmel focused on their T cell program, which targets infectious diseases by improving resilience. “There’s an enormous number of possible combinations,” he said. “We can’t experiment our way through that, so we need to be both efficient and smart about which experiments we choose.”</p> <p style="text-align: justify;">To solve this problem, New Limit has developed a proprietary high-throughput discovery process that begins with predictive computer models. The work then moves into primary human cells from multiple young and old donors.</p> <p style="text-align: justify;">When the researchers introduce pools of transcription factors, “due to the stochasticity of delivery, each cell picks up a different subset of factors,” Kimmel explained. “The result is a dish where all possible subcombinations up to a certain number are represented. We’ve attached DNA barcodes to these factors, allowing us to use single-cell genomics downstream to measure what happened – which genes the cell is expressing and which transcription factors achieved that outcome.”</p> <p>To detect if any combination resulted in rejuvenation, the researchers use machine learning models to predict cell age from gene expression profiles. Using this system, they have screened around 9,000 combinations of transcription factors for their effect on cell age – “about 500 times more than the roughly 19 combinations tested in academic literature,” Kimmel said.</p> <p style="text-align: justify;">Interestingly, the researchers have found that many different transcription factors can reverse T cell aging, often to the same degree as the Yamanaka factors. That said, those factors were not just variants of Yamanaka’s but are “broadly distributed across different transcription factor families, suggesting multiple paths to reprogram cell age.” Kimmel reported seeing a lot of synergy as if transcription factors tend to work better in combinations.</p> <p><img loading="lazy" decoding="async" class="aligncenter size-full wp-image-134078" src="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5.png" alt="GSA2024 5" width="1000" height="523" srcset="https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5.png 1000w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-400x209.png 400w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-745x390.png 745w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-256x134.png 256w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-300x157.png 300w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-150x78.png 150w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-480x251.png 480w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-600x314.png 600w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-360x188.png 360w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-262x137.png 262w, https://www.lifespan.io/wp-content/uploads/2024/11/GSA2024-5-555x290.png 555w" sizes="(max-width: 1000px) 100vw, 1000px"></p> <p style="text-align: justify;">Rejuvenation apparently leads to improved T-cell fitness. “We found canonical cytotoxicity functions of human T cells are significantly impaired with age – something not clearly established in the literature before our work,” Kimmel said. However, the team has found many novel combinations that restore T cells’ fitness even stronger than the Yamanaka factors.</p> <p style="text-align: justify;">The question of durability, according to Kimmel, is crucial – effects that only last while mRNAs are expressed would be difficult to translate into treatments. “But we found that some combinations produce durable changes, measurable many days after turning off the factors,” he said.</p> <h2 style="text-align: justify;"><b>Y is this happening?</b></h2> <p style="text-align: justify;">Nick Chavkin, Assistant Professor at the Department of Pediatrics at Seattle Children’s Research Institute (hence, a local), gave a talk about a particularly interesting mutation affecting blood cells: the loss of the Y chromosome. Due to hematopoietic clonal expansion (when hematopoietic stem cells with certain mutations become more successful in reproduction and, as a result, dominate the cell pool), this mutation is quite prevalent in aged people, but for obvious reasons, only in men. According to the UK Biobank, by age 70, about 45% of men show appreciable Y chromosome loss, which, according to Chavkin, makes it the most common known human post-zygotic mutation.</p> <p style="text-align: justify;">Large biobank datasets also revealed the link between this long-known condition and all-cause mortality. Men with Y chromosome loss are about twice as likely to die at any given age compared to men without Y loss.</p> <p style="text-align: justify;">“The first associations were with cancer mortality and Alzheimer’s disease diagnosis – men with Y loss show higher rates of both,” Chavkin said. “We also demonstrated an increased rate of cardiovascular disease. This led us to investigate the mechanistic aspects. While the correlations are interesting, we wanted to know: could Y loss actually promote these disease states, or is it just an age-related phenomenon associated with genomic instability?”</p> <p style="text-align: justify;">The researchers created a mouse model with 80-90% Y-loss in hematopoietic stem cells. Compared to controls, those mice showed diminished survival, age-related cardiomyopathy, pulmonary and renal fibrosis, and cognitive decline: all the known hallmarks of Y loss.</p> <p style="text-align: justify;">Y-loss mice also showed exacerbated heart failure conditions. Looking for mechanistic explanations, the researchers discovered that Y-loss macrophages have a preference for fibrotic polarization, unlike some other known clonal mutations that promote inflammation.</p> <p style="text-align: justify;">Chavkin’s team then looked for the specific Y chromosome genes that drive these effects. “This was relatively straightforward because the Y chromosome is often considered a genetic “wasteland” post-puberty,” Chavkin said. “In mouse macrophages, only four Y chromosome genes are appreciably expressed, all within about a million base pairs: KDM5D, EIF2S3Y, UTY, and DDX3Y.”</p> <p style="text-align: justify;">Three knockouts had no effect, but UTY knockout recapitulated the full Y-loss phenotype. UTY is an epigenetic modifier that probably has broad regulatory effects.</p> <p style="text-align: justify;">Further experiments suggested that UTY inhibits pro-fibrotic macrophage polarization by regulating genomic DNA accessibility. UTY knockout probably allows certain transcription factors to bind and promote this polarization, leading to fibrosis.</p> <p style="text-align: justify;">The team’s current hypothesis is that Y chromosome loss leads to UTY insufficiency in monocytes. This increases chromatin accessibility for pro-fibrotic genes, allowing fibrotic transcription factor activity and ultimately leading to pro-fibrotic polarization and myocardial fibrosis.</p> <p style="text-align: justify;">“In summary, Y chromosome loss appears to be an age-related somatic mutation contributing to male mortality,” Chavkin said. “Our work suggests UTY plays a key role in this process. 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Dietary restriction or good genes: new study tries to unpick which has a greater impact on lifespan

<p>As people who research ageing like to quip: the best thing you can do to increase how long you live is to pick good parents. After all, it has long been recognised that longer-lived people tend to have longer-lived parents and grandparents, suggesting that genetics influence longevity. </p> <p>Complicating the picture, however, is that we know that the sum of your lifestyle, specifically <a href="https://pubmed.ncbi.nlm.nih.gov/37985698/">diet</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395188/">exercise</a>, also significantly influences your health into older age and how long you live. What contribution lifestyle versus genetics makes is an open question that a <a href="https://www.nature.com/articles/s41586-024-08026-3">recent study</a> in Nature has shed new light on. </p> <p>Scientists have long known that reducing calorie intake can make animals live longer. In <a href="https://www.sciencedirect.com/science/article/abs/pii/S0022316623189899">the 1930s</a>, it was noted that rats fed reduced calories lived longer than rats who could eat as much as they wanted. Similarly, people who are more physically active tend to live longer. But specifically linking single genes to longevity was until recently a controversial one. </p> <p>While studying the lifespan of the tiny worm <em>C elegans</em> at the University of California, San Francisco, <a href="https://www.pnas.org/doi/10.1073/pnas.1114658108">Cynthia Kenyon</a> found that small changes to the gene that controls the way that cells detect and respond to nutrients around them led to the worms doubling their lifespan. This raises new questions: if we know that genetics and lifestyle affect how long you live, which one is more important? And how do they interact? </p> <p>To try to tease out the effects of genetics versus lifestyle, the new study in Nature examined different models of caloric restriction in 960 mice. The researchers specifically looked at classical experimental models of caloric restriction (either 20% or 40% fewer calories than control mice), or intermittent fasting of one or two days without food (as intermittent fasting is popular in people looking to see the positive benefits of caloric restriction). </p> <p>Because we now know that small genetic variations affect ageing, the researchers specifically used genetically diverse mice. This is important for two reasons. First, as laboratory studies on mice are normally performed on genetically very (very!) similar mice, this allowed the researchers to tease out the effects of both diet and genetic variables would have on longevity. </p> <p>Second, humans are highly diverse, meaning that studies on genetically near-identical mice don’t often translate into humanity’s high genetic diversity.</p> <p>The headline finding was that genetics appeared to play a larger role in lifespan than any of the dietary restriction interventions. Long-lived types of mice were still longer lived despite dietary changes. </p> <h2>Diet counts, but genes count more</h2> <p>And while shorter-lived mice did show improvements as a result of dietary restrictions, they didn’t catch up to their longer-lived peers. This suggests that there’s truth to the “pick good parents” joke. </p> <p>Caloric restriction models still increased lifespans across all the types of mice, with the 40% restriction group having improved average and maximum lifespans compared with the 20% group. </p> <p>And the 20% group showed improvements in both group average and maximum length of lives compared with the control group. It’s just the effects of genetics were larger than the effect of the dietary interventions.</p> <p>While all the caloric restriction models resulted in increased lifespan in the mice on average, in the most extreme caloric restriction model tested (40% less group) changes that could be seen as physical harms were observed. These included reduced immune function and losses in muscle mass, which outside of a predator- and germ-free laboratory environment could affect health and longevity.</p> <p>There are some important caveats in studies like this. First, it’s not known if these results apply to humans. </p> <p>As with most caloric restriction research in mice, the restricted feeding groups were fed 20% or 40% less than a control group who ate as much as they wanted. In humans, that’d be like assuming people eating every meal every day at a bottomless buffet is “normal”. And people who do not eat from limitless trays of food are “restricted feeding”. That’s not an exact parallel to how humans live and eat.</p> <p>Second, although exercise wasn’t controlled in any way in this study, most groups did similar amounts of running in their in-cage running wheels except the 40% caloric restriction group who ran significantly more. </p> <p>The researchers suggested that this extra exercise in the 40% group was the mice constantly hunting for more food. But as this group did so much more exercise than the others, it could also mean that positive effects of increased exercise were also seen in this group alongside their caloric restriction.</p> <p>So, while we can’t pick our parents or change the genes we inherit from them, it is interesting to know that specific genetic variations play a significant role in the maximum age we can aspire to. </p> <p>The genetic cards we’re dealt dictate how long we can expect to live. Just as important in this study, however, lifestyle interventions such as diet and exercise that aim to improve lifespan should be effective regardless of the genes we have.</p><img src="https://counter.theconversation.com/content/241050/count.gif" alt="The Conversation" width="1" height="1" /> <p class="fine-print"><em><span>Bradley Elliott receives funding from the Physiological Society, the British Society for Research on Ageing, the Altitude Centre, and private philanthropic individuals, and has consulted for industry and government on longevity research. He is on the Board of Trustees of the British Society for Research on Ageing. </span></em></p>