A Core Senescence Biomarker Fights Inflammation

Date Posted: March 20, 2025

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A Core Senescence Biomarker Fights Inflammation

Researchers publishing in Nature Communications have found that p53, a biomarker and inducer of senescence, suppresses both inflammation and DNA damage in senescent cells.

Senescence against cancer

Cellular Senescence is one of the proposed reasons we age.

Why We Age: Cellular Senescence

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 ...
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One of the main reasons why cells become senescent is to prevent cancer. The senescence-inducing compound p53, in particular, is known in the literature as a tumor suppressor, and its presence has been found to reduce, rather than exacerbate, the SASP [1]. The biochemical reasons behind this seemingly contradictory connection have not been previously explained.

However, these researchers have previously found that a biochemical pathway from the mitochondria to the nucleus is partially responsible for driving the SASP [2]. This pathway drives the expulsion of chromatin from the nucleus into the rest of the cell, which activates the cGAS/STING pathway and thus turns on NF-κB, the SASP’s master regulator [3]. Therefore, they sought to determine a link between p53 and this well-established pathway.

Preventing the SASP at its root

For their first experiment, the researchers created fibroblasts in which 53BP1, a suppressor of DNA damage that works with p53, was somewhat increased. These fibroblasts, after they were driven senescent through irradiation, had reduced amounts of chromatin in the nucleus and, thus, less SASP. Driving cells senescent by introducing p53 had similar effects, as did knocking down its target, MDM2.

Mutating 53BP1, on the other hand, had significant negative effects, spurring the release of chromatin into the nucleus after the cells were driven senescent with radiation. Silencing p53 had similar effects; four days after irradiation, cells with silenced p53 had significantly more chromatin in the nucleus. Further work found that mitochondria are required for this SASP upregulation; ablating away mitochondria prevented the chromatin from being expelled into the nucleus and thus prevented the upregulation of SASP elements.

Protecting cells from DNA damage

p53 was also found to be instrumental in DNA repair. γH2AX is a marker of DNA damage, and its levels in the nucleus were reduced in cells where MDM2 was downregulated and p53 was upregulated. The researchers found that this could be accomplished by introducing RG7388, a compound that promotes p53.

Similarly, silencing p53 increased the prevalence of this DNA damage marker. Interestingly, p21, another well-known biomarker of senescence, was found to be necessary for the effects of p53; without p21 being present, neither MDM2 nor p53 made any difference.

This was not just a change in a biomarker; p53 had real effects on the genome. In cells treated with RG7388 shortly after irradiation, the number of DNA amplifications and deletions was relatively small. In untreated cells, however, these signs of genetic damage were rampant. Most of this damage was located near the ends of the chromosomes, where the telomeres are. Unlike with chromatin ejection, however, mitochondria had nothing to do with these DNA damage effects.

Effects in female mice

The researchers then turned to in vivo experiments, introducing HDM201, a compound that suppresses MDM2, to a population of naturally aged mice for two weeks. In both males and females, HDM201 had no effects on body weight, blood cell counts, or liver pathological biomarkers. However, as the liver is where senescent cells normally accumulate in mice [4], the researchers focused their attentions there. Both p53 and p21 were significantly increased in these mice.

Interestingly, in gene expression, this treatment had substantially greater effects on female mice than on male mice. While it had no senolytic effects, it reversed many of the gene expression changes caused by aging. As expected, many of these genes were related to the SASP, and, likewise, the number of immune cells that infiltrated into these mice’s livers was decreased as well.

Both p53 and p21 have been investigated in the context of senescence, with previous researchers considering them as potential targets to be suppressed. This work, however, demonstrates that these compounds are both necessary and beneficial for preventing senescent cells from getting out of control. The researchers describe p53 as a senomorphic compound; while it clearly does not remove senescent cells, it significantly blunts their negative effects on the cells around them. They hold that “it may be possible to one day design a treatment that targets p53 to promote healthier aging.”

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Literature

[1] Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y. U., Muñoz, D. P., Goldstein, J., … & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6(12), e301.

[2] Vizioli, M. G., Liu, T., Miller, K. N., Robertson, N. A., Gilroy, K., Lagnado, A. B., … & Adams, P. D. (2020). Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes & development, 34(5-6), 428-445.

[3] Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., … & Berger, S. L. (2017). Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature, 550(7676), 402-406.

[4] Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., … & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nature communications, 8(1), 15691.

Date Posted: March 19, 2025

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A Hypothalamus Neuropeptide Reduces Aging in a Mouse Model

Researchers have improved multiple health metrics in prematurely aged mice by re-establishing the production of neuropeptide Y in the hypothalamus [1].

An essential protein

Age-related decline in the function of the hypothalamus, a core region of the brain, has been suggested to be a “key factor in the development of whole-body aging” [2]. Due to its essential role and implication in several aging-related processes, the hypothalamus may be a target for lifespan- and healthspan-extending therapeutic strategies.

The authors of this study focused specifically on hypothalamic neuropeptide Y (NPY). Several studies suggest that neuropeptide Y plays a role in lifespan through its involvement in lifespan-extending processes such as autophagy induction [3] and stress resistance [4], and it appears to play an essential role in caloric restriction-induced lifespan extension [5, 6]. Decreased levels have been connected to neurodegenerative diseases [7]. Therefore, the authors hypothesized whether re-establishing hypothalamic neuropeptide Y levels might slow down aging.

Aging too quickly

For this study, the researchers used animals that lack a gene encoding the protein Zmpste24 (Z24-KO), and this lack results in accelerated aging and premature death. Z24-KO mice have multiple defects in skin, bone, cardiovascular tissues, and skeletal muscles, similar to those observed in human accelerated aging processes. Therefore, the authors decided to test if their hypothalami exhibit the same changes as the hypothalami of naturally aged mice.

They tested an area of the hypothalamus called the arcuate nucleus (ARC), which contains neurons that release neuropeptide Y. They found lower levels of neuropeptide Y compared to age-matched wild-type mice and lower levels of a neuronal marker called NeuN, suggesting neuronal aging and fewer hypothalamic neurons.

Markers connected to neuroinflammation were also altered. The authors observed increased levels of a gliosis marker in Z24-KO mice. Gliosis is a process that occurs in glial cells (non-neuronal cells located in the central nervous system) in response to damage. Therefore, an increase in gliosis suggests neuroinflammation. On the other hand, a marker showing the activity of microglia, the immune cells of the brain, decreased in Z24-KO mice. This, according to the authors, suggests that immune response capacity is impaired.

Restoring youth

To re-establish decreased neuropeptide Y levels, the researchers used a genetically modified adeno-associated virus (AAV) that causes an increase in the expression of neuropeptide Y (AAV-NPY) and injected it into the mice. The virus increased neuropeptide Y in the ARC for at least four months, which is when the mice were sacrificed to analyze their organs.

The researchers tested the AAV-treated Z24-KO mice for the same biomarkers as the untreated Z24-KO mice. They observed an increase in NeuN and a reduction of the gliosis biomarker that is normally elevated in these mice. However, the biomarker of microglial immune capacity didn’t significantly change. Overall, AAV treatment made the brains of Z24-KO mice similar to those of age-matched wild-type mice, suggesting that neuropeptide Y plays a role in reducing neuroinflammation.

Further testing suggested positive changes in aging-related processes. The authors observed a reduction in NF-κB, a protein that increases with aging and is associated with neuroinflammation in the hypothalamus [8]. Other positive effects were a decrease in a marker of tau pathology, which is associated with neurodegenerative diseases [9], and an increase in autophagy, a process that plays an essential role in longevity.

Better looks and healthier minds

The authors also report positive changes in body weight, body composition, mobility, vitality, and fur among the virus-treated animals. The treatment also showed neuroprotective effects, as the spatial memory improvements accompanied physical health improvements, but there were no significant differences in locomotor activity.

One of the characteristics of the prematurely aged Z24-KO mice is lipodystrophy. This condition results in the organism losing fat from some parts of the body, including under the skin surface of different body parts, while gaining it in others, such as the liver.

The AAV-treated mice had fewer lipodystrophy symptoms. The treatment resulted in a thicker outermost skin layer (epidermis) and thicker layers of under-skin (subcutaneous) fat, probably resulting from increased proliferation of fat cells as suggested by increased levels of a cell proliferation marker. It also increases skin collagen, which decreases with age. Autophagy markers in the skin indicated increased autophagic activity, suggesting better cellular health.

Liver structure was also improved in the Z24-KO mice after treatment. The researchers observed increased cell proliferation, which might indicate improved liver protection and regeneration, a decrease in cellular death by apoptosis, and increased autophagic activity in the liver, suggesting better cellular health.

There were no differences between treated and untreated mice in different parameters of kidney health and heart structure, but heart cells showed improved cellular health.

Promising, but there are still many unknowns

Overall, this study’s results suggest that re-establishing neuropeptide Y has a positive effect on aging-associated hypothalamus-related symptoms. However, in most of the experiments performed, the researchers compared untreated, prematurely aged mice to prematurely aged mice treated with a virus expressing neuropeptide Y. It would be beneficial if a wild-type control was included, as this would allow for assessing whether the observed changes make the prematurely aged mice more similar to wild-type mice or if the changes are significant but modest.

Additionally, long-term studies are essential to determine the long-lasting effects and side effects of this approach, whether it induces the desired amount of neuropeptide Y expression, and how improvements in different biomarkers of cellular health translate to increases of healthspan and lifespan.

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Literature

[1] Ferreira-Marques, M., Carmo-Silva, S., Pereira, J., Botelho, M., Nóbrega, C., López-Otín, C., de Almeida, L. P., Aveleira, C. A., & Cavadas, C. (2025). Restoring neuropetide Y levels in the hypothalamus ameliorates premature aging phenotype in mice. GeroScience, 10.1007/s11357-025-01574-0. Advance online publication.

[2] Kim, K., & Choe, H. K. (2019). Role of hypothalamus in aging and its underlying cellular mechanisms. Mechanisms of ageing and development, 177, 74–79.

[3] Aveleira, C. A., Botelho, M., Carmo-Silva, S., Pascoal, J. F., Ferreira-Marques, M., Nóbrega, C., Cortes, L., Valero, J., Sousa-Ferreira, L., Álvaro, A. R., Santana, M., Kügler, S., Pereira de Almeida, L., & Cavadas, C. (2015). Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proceedings of the National Academy of Sciences of the United States of America, 112(13), E1642–E1651.

[4] Michalkiewicz, M., Knestaut, K. M., Bytchkova, E. Y., & Michalkiewicz, T. (2003). Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension (Dallas, Tex. : 1979), 41(5), 1056–1062.

[5] Chiba, T., Tamashiro, Y., Park, D., Kusudo, T., Fujie, R., Komatsu, T., Kim, S. E., Park, S., Hayashi, H., Mori, R., Yamashita, H., Chung, H. Y., & Shimokawa, I. (2014). A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction. Scientific reports, 4, 4517.

[6] de Rijke, C. E., Hillebrand, J. J., Verhagen, L. A., Roeling, T. A., & Adan, R. A. (2005). Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats. Journal of molecular endocrinology, 35(2), 381–390.

[7] Duarte-Neves, J., Pereira de Almeida, L., & Cavadas, C. (2016). Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiology of disease, 95, 210–224.

[8] Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., & Cai, D. (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497(7448), 211–216.

[9] Samudra, N., Lane-Donovan, C., VandeVrede, L., & Boxer, A. L. (2023). Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues. The Journal of clinical investigation, 133(12), e168553.

Date Posted: March 18, 2025

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Short-Term Overeating Alters Brain Insulin Sensitivity

A new study published in Nature Metabolism suggests that even a short period of eating loads of sweet and fatty snacks can cause brain changes reminiscent of those seen in obesity and type 2 diabetes [1].

What can go wrong in five days?

If you usually eat healthy and take care of your body, there’s no harm in letting your guard down for a while, right? Not so fast, says a new study by the University Hospital of Tübingen, the German Center for Diabetes Research (DZD), and Helmholtz Munich.

This controlled but not randomized study recruited 29 young, healthy men with a normal body mass index (BMI). At baseline, there was no significant difference between the study group and the control group in terms of calories and nutrients consumed. Participants in the study group were asked to increase their daily calorie intake by 1,500 calories for five days by consuming highly processed sweet and fatty snacks. The researchers measured various biomarkers at baseline, after five days of the experiment, and one more week later.

Altered insulin responses

They found that even though body mass did not significantly change in the study group compared to controls, the unhealthy diet caused a noticeable increase in liver fat contents. Probably more intriguing results related to how the participants’ brains reacted to this ‘food assault.’ While insulin directly stimulates glucose uptake in muscle and fat cells, its role in the brain is different: it helps regulate appetite, metabolism, and cognitive functions related to food choices. The “brain first” hypothesis postulates that those reactions play an important role in the development of insulin resistance and related metabolic disorders.

Immediately after the five days of the experiment, the study group showed increased insulin responses in reward-related brain regions (insula, midbrain). This pattern has been previously observed as an early response to overeating [2] – conceivably, to make food less attractive. However, if the system “overshoots,” the dampened reward response might cause the person to eat more to get to the same level of satisfaction. The changes in the reward and punishment responses were evident in a series of cognitive experiments that the researchers conducted.

Some researchers suggest that heightened insulin activity could eventually lead to insulin resistance if healthy eating habits are not restored, though this remains to be confirmed. Indeed, in this study, one week after resuming a normal diet, the brain insulin responsiveness of the hippocampus and fusiform gyrus was reduced in the study group. These two brain regions are important for memory and cognition, including food-related decision-making. Earlier studies have found comparable reductions in brain insulin responsiveness in people with obesity and type 2 diabetes [3].

“Our findings demonstrate for the first time that even a brief consumption of highly processed, unhealthy foods (such as chocolate bars and potato chips) causes a significant alteration in the brain of healthy individuals, which may be the initial cause of obesity and type 2 diabetes,” said Dr. Stephanie Kullmann, the study’s lead author. “Interestingly, in our healthy study participants, the brain shows a similar decrease in sensitivity to insulin after a short-term high calorie intake as in people with obesity. This effect can even be observed one week after returning to a balanced diet.”

Is it “brain first”?

While the participants in the study group did return to their normal eating habits, this might be because they knew they were temporarily overeating as part of an experiment, not as a personal choice. This awareness likely made it easier for them to consciously give up overeating. People who start overeating in less controlled settings, such as in emotional distress, might not be so lucky.

Importantly, the researchers did not find signs of impaired peripheral insulin signaling, suggesting that brain insulin dysfunction may occur before systemic changes. This finding is in line with the “brain first” hypothesis, which suggests that brain insulin resistance may precede whole-body metabolic dysfunction. However, more rigorous studies are needed to confirm or disprove this.

The study had several important limitations, such as the small sample size and short follow-up duration. The scientists chose to limit participation to males because previous research has shown differences in insulin dynamics in males and females. However, this also affected the study’s generalizability and interpretability.

Dr. Andreas Birkenfeld, the study’s co-author, concluded, “We assume that the brain’s insulin response adapts to short-term changes in diet before any weight gain occurs and thus promotes the development of obesity and other secondary diseases.”

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Literature

[1] Kullmann, S., Wagner, L., Hauffe, R., Kühnel, A., Sandforth, L., Veit, R., … & Birkenfeld, A. L. (2025). A short-term, high-caloric diet has prolonged effects on brain insulin action in men. Nature Metabolism, 1-9.

[2] Wingrove, J. O., O’Daly, O., Forbes, B., Swedrowska, M., Amiel, S. A., & Zelaya, F. O. (2021). Intranasal insulin administration decreases cerebral blood flow in cortico‐limbic regions: A neuropharmacological imaging study in normal and overweight males. Diabetes, Obesity and Metabolism, 23(1), 175-185.

[3] Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H. Y., Ahima, R. S., … & Nathan, D. M. (2018). Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature Reviews Neurology, 14(3), 168-181.

Date Posted: March 17, 2025

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Elamipretide, a Potential New Drug, Reduces Frailty in Mice

In Aging Cell, Dr. Vadim Gladyshev and a team of researchers have described how elamipretide beneficially affects mitochondrial pathways and reverses frailty in mice.

A drug on its way to the clinic

As a mitochondria-affecting antioxidant peptide, elamipretide has been, and continues to be, the subject of multiple investigations. As far back as 2004, researchers were testing whether its effects against reactive oxygen species (ROS) had benefits against ischemia-reperfusion injury [1], which occurs when blood is restored to tissue after it has been cut off, such as when a heart attack is treated. Other work has used it to treat heart failure in dogs [2]. Right now, Stealth Biotherapeutics is waiting for the FDA to approve it as a new drug for treating Barth syndrome, a rare mitochondrial disease.

Despite its clinical benefits, it has been little investigated in the context of aging biomarkers. Theoretically, a drug that has significant benefits for people suffering mitochondrial disorders and age-related diseases would similarly improve known biomarkers, such as epigenetic clock measurements and, relatedly, gene expression. These researchers, therefore, attempted to investigate if that is the case.

What elamipretide affects

The first experiment described in this paper tested function in 5-month-old and 24-month-old Black 6 mice, both males and females. Osmotic pumps under the mice’s skin delivered elamipretide for 8 weeks, after which the mice were tested and examined again.

The frailty index, a measurement of flaws in overall physical function that is often used to diagnose age-related weakness, was decreased in older mice of both sexes that had received elamipretide, despite being two months older at the end of the study. Heart function, as measured by ejection fraction and pumping force, was significantly improved. There were also benefits against fatigue, particularly in females.

Multiple molecular pathways received significant benefits. As expected of a drug that treats the mitochondria, many of the affected pathways were related to mitochondria organization and transport along with ATP production and oxygen processing. Immunological pathways that are upregulated with aging were downregulated with elamipretide, suggesting some benefits against inflammaging.

What elamipretide doesn’t affect

The heart enlarges with age, and elamipretide did nothing to ameliorate this. The mass of the gastrocnemius, a crucial muscle in the leg, was unaffected. Despite its effects on frailty, it did not appear to have consistently significant effects on overall skeletal muscle force; it appeared to increase maximum force in older female mice while decreasing maximum force in older male mice.

Most interestingly, despite the effects on pathways, there were no effects on differentially expressed genes related to aging. Aging clocks, including transcriptomic clocks and the Horvath epigenetic clock, were used on multiple tissues, and none of them revealed any difference; the old treated mice, despite being significantly less frail, did not become biologically younger. While there appeared to be trends towards gene expression that are similar to the effects of rapamycin, these findings were not statistically significant.

Similarly, although there were a couple of findings involving effects on cap-independent translation targets, which are alternate metrics of longevity, the researchers hold that these unclear results were largely negligible and that elamipretide does not, overall, have significant effects on molecular longevity predictors.

This study sheds light on the difference between functional benefits and biomarker metrics, potentially revealing the limitations of clocks. Elamipretide may have no benefits against epigenetic aging, but it has clear benefits for the mitochondria, and it is poised to reach the clinic. Further clinical determinations will reveal if it is effective against frailty in human beings.

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Literature

[1] Zhao, K., Zhao, G. M., Wu, D., Soong, Y., Birk, A. V., Schiller, P. W., & Szeto, H. H. (2004). Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry, 279(33), 34682-34690.

[2] Sabbah, H. N., Gupta, R. C., Kohli, S., Wang, M., Hachem, S., & Zhang, K. (2016). Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circulation: Heart Failure, 9(2), e002206.

Date Posted: March 14, 2025

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LongX Launches 2nd Edition of the Xplore Program

LongX, an initiative dedicated to providing avenues into the longevity space, announced a call for applications for the 2025 Xplore Program. With its inaugural cohort launching last year, the Xplore Program is a remote fellowship open to early career professionals and students looking for their first steps in longevity biotechnology. The 2nd edition will take place from June 2025 to August 2025, and features 1 month of aging biology and biotechnology courses followed by the opportunity to gain industry experience with partnered biotech companies for 2 months.

Xplore Program fellows will receive guidance from working professionals in longevity while also having the opportunity to network with peers and experts. The fellowship is accepting applications until March 31, 2025.

To learn more, visit LongX or apply directly to the Xplore Program.

About LongX

Longevity Xplorer (LongX) was formed in 2023 to lower the barrier of entry for emerging early career professionals in longevity. Our goal is to drastically increase the number and capacity of people who meaningfully contribute to the longevity industry on a global scale. We encourage exploration beyond traditional roles and aim to equip future experts with the skills to drive progress in the field. The LongX Substack is home to various articles and interviews showcasing developments within the longevity space, resources, opportunities, experiences, and advice.

Contact

Marvin Yan, Co-Founder

team@longx.bio

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Date Posted: March 14, 2025

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Using a Surface Biomarker to Target Senescent Cells

Scientists have identified a senescence-associated surface protein that can be targeted using antibodies [1]. This discovery might help distinguish between beneficial and harmful senescent cells and could speed up the development of senolytic therapies. This work was done by the Lifespan Research Institute, which was formed last year by the merger of SENS Research Foundation and Lifespan.io.

Shedding light on senescence

Most geroscientists agree on two things: cellular senescence is an important driver of aging, and senescent cells are notoriously difficult to study and target because of their heterogeneity. Senescent cells are often described as damaged or exhausted cells that stop dividing but remain alive, releasing pro-inflammatory factors that can induce senescence in neighboring cells. While cellular senescence plays a beneficial role in some processes related to development, wound healing, and anti-cancer surveillance, the overall senescence burden grows with age, tipping the scale towards harm.

Why We Age: Cellular Senescence

The answer is on the surface

Senescent cells are known to exhibit increased lysosomal activity [2]. Lysosomes are bubble-like organelles that envelop intracellular junk and transport it outside the cell by fusing with the cell’s outer membrane in a process called lysosomal exocytosis. The underlying causes of excessive intracellular waste in senescent cells are not entirely clear, but this process may contribute to senescence-related inflammation.

Working with a publicly available database of membrane proteins, the researchers zeroed in on the protein LAMP1, which is abundant in lysosomal membranes. In healthy cells, “LAMP1 is only briefly found at the cell surface due to the fusion of lysosomes with the plasma membrane, and thus, mostly undetectable,” the paper says. However, LAMP1 is known to linger in membranes of some cancer cells, probably due to their increased lysosomal exocytosis.

The dataset revealed a strong correlation between LAMP1 expression and other known senescence-related genes, such as p21 and p16, but the researchers had to confirm this in actual cells. After inducing senescence in human fetal lung fibroblasts in three different ways, they observed a significant increase in the proportion of LAMP1-positive cells. While only about 1% of untreated cells expressed LAMP1 on their membranes, 20% to 60% of treated cells expressed it, depending on how senescence was induced.

The researchers then isolated both LAMP1-positive and LAMP1-negative cell populations from the liver and lungs of middle-aged mice and found that the former expressed additional senescence markers.

Telling good from evil

As their in vivo model, the researchers chose mice treated with bleomycin, which induces a condition similar to idiopathic pulmonary fibrosis (IPF) – a deadly and currently uncurable age-related lung disease. IPF has long been suspected to be driven by increased cellular senescence.

Experiments detected a 1.5- to 3-fold increase in the number of LAMP1-positive cells after the bleomycin treatment relative to controls. Interestingly, in healthy mice, LAMP1 was expressed mostly by a fraction of one cell type: endothelial cells. In contrast, bleomycin-treated mice showed LAMP1 expression across multiple cell types.

This difference might be important for distinguishing between beneficial and harmful senescent cells. “Another interesting observation is that in healthy mice, most senescent cells in the lung were endothelial cells,” said Dr. Amit Sharma, who led the study. “In contrast, in bleomycin-treated mice that showed increased inflammation, the majority of senescent cells were of myeloid origin. It is possible that another layer of complexity in the heterogeneity of senescence is the type of cells contributing to pathology vs tissue repair.”

He further explained, “There has been a discussion of good vs bad senescent cells, so is it possible that these myeloid senescent cells are the bad ones? There is some evidence by others that this might be true, at least in liver fibrosis [3], where eliminating p16-expressing fibroblasts slows down tissue repair, while p16-expressing macrophages can be beneficial. Of course, this must be further tested. If LAMP1 is reliably seen as a senescence biomarker, we can develop drugs specifically targeting bad senescent cells, which would be safer.”

Targeting LAMP1

Lastly, the researchers made the first steps towards confirming LAMP1 as a possible target for intervention. Working on cells in culture, they used an antibody-drug conjugate (ADC), a construct consisting of an antibody that targets a specific surface protein, in this case LAMP1, and a drug that kills the targeted cell (technically, the ADC targeted another antibody, which targeted LAMP1). The treatment caused substantial cytotoxicity in senescent cells and virtually none in non-senescent cells.

According to Sharma, identifying LAMP1 as a surface biomarker of senescence is significant. Unlike cytosolic markers that remain inside the cell, surface biomarkers might allow easier detection, study, and targeting of senescent cells.

“Senescent cell biomarker discovery is the holy grail of senescence research,” Sharma said. “This will be useful for understanding how senescent cells contribute to pathology and validating the efficacy of interventions. If what we found in the IPF mouse model and in middle-aged mice is true for other senescence models, a surface marker offers a huge possibility for diagnostic tool development.”

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Literature

[1] Meca-Laguna, G., Qiu, M., Hou, Y., Barkovskaya, A., Shankar, A., Dixit, B., Rae, M. J., Boominathan, A., & Sharma, A. (2025). Cell-Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis. Aging cell, e70141. Advance online publication.

[2] Rovira, M., Sereda, R., Pladevall‐Morera, D., Ramponi, V., Marin, I., Maus, M., … & Serrano, M. (2022). The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging Cell, 21(10), e13707.

[3] Zhao, H., Liu, Z., Chen, H., Han, M., Zhang, M., Liu, K., … & Zhou, B. (2024). Identifying specific functional roles for senescence across cell types. Cell, 187(25), 7314-7334.

Date Posted: March 13, 2025

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Cellular Senescence Prevents Unlearning in Some Male Mice

In Aging Cell, researchers have established a link between cellular senescence and cognitive decline in unmodified male mice.

Resilience versus decline

The authors begin their paper by noting that cognitive decline in older people varies greatly. Some people suffer serious cognitive defects; other people are scarcely impacted at all [1]. The researchers have developed an automated tool called PhenoTyper to measure this in unmodified male Black 6 mice, establishing a benchmark set at 5 to 7 months old and using it to classify older mice as either intact or impaired [2]. They previously used this benchmark to ascertain that some mice remain fully functioning throughout their lives while others suffer serious cognitive decline [3].

This decline has nothing to do with Alzheimer’s, which wild-type mice cannot get. Instead, the researchers point to reactive gliosis, which, under normal circumstances, is the brain’s response to injury [4]. Sustained, chronic inflammation in aging is known as inflammaging, and sustained reactive gliosis is this process in the brain. The same compounds that are responsible for systemic inflammaging, such as the senescence-associated secretory phenotype (SASP), occur in the brain as well, and previous work has found that removing these cells leads to cognitive benefits [5].

However, these researchers hold that such previous work did not adequately distinguish between cognitively impaired and intact mice. Therefore, they performed an experiment of their own, attempting to more thoroughly document the relationship between brain senescence and cognitive decline.

Teaching old mice new tricks

For their first experiment, the researchers used their PhenoTyper system to assess the capabilities of their mice. In this experiment, mice were taught for 50 hours that they must enter the leftmost hole of a three-hole setup in order to receive food pellets; for another 40 hours, however, they had to use the rightmost hole instead (“reversal learning”).

In learning the initial hole, young (6 months) mice and old (22 to 24 months) mice performed similarly well. However, in the reversal learning task, there was an immense amount of difference between the two groups; the older mice’s performance was bimodal, with some older mice completely failing to unlearn what they had learned.

These dramatic differences within the aged group were not related to the total distance moved by the mice, nor were they related to changes in circadian rhythms (this test was performed during the dark hours in which mice are most active). They also only applied to male mice; female mice did not have a similarly sharp stratification.

The researchers then examined the differences between these stratified groups. They found substantial and stark differences in both morphology and in biochemistry. Microglial activity was greatly increased in the impaired group, while the intact group was indistinguishable in this area from younger mice. Some biomarkers of reactive gliosis were moderately increased in the intact group, but all of them were far more elevated in the impaired group. These researchers, therefore, hold that they have found a distinct phenotype of neurological impairment.

This was linked to biomarkers of cellular senescence. Interestingly, the p16 senescence biomarker, which was significantly more elevated in intact older mice compared to young mice, was only slightly more elevated in the impaired group. p21 was nearly the same in both older groups and elevated compared to younger mice. However, other biomarkers were significantly different. The interleukin IL-6 was notably upregulated only in the impaired group, as was the key senescence marker SA-β-gal.

Senolytics appear to help

The researchers then administered the well-known senolytic combination of dasatinib and quercetin (D+Q) to 22-month-old mice and performed cognitive tests at 24 months. Nearly all the older animals given the senolytic were considered cognitively intact mice, with very few failing the reversal learning task. Their senescent cell biomarkers were similarly reduced to those of intact mice, with IL-6 reaching approximately the level of young mice; similar beneifits were found in microglial morphology and biochemistry. Once again, these findings only applied to males.

The researchers surmise that such sex-related differences may also apply to human beings. Additionally, this work applies specifically to ‘normal’ cognitive decline that may not be directly related to proteostasis diseases such as Alzheimer’s. However, if a relevant human population can be identified, a senolytic or senomorphic regimen may allow them to retain their cognitive abilities.

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Literature

[1] Marron, M. M., Wojczynski, M. K., Minster, R. L., Boudreau, R. M., Sebastiani, P., Cosentino, S., … & Long Life Family Study. (2019). Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism. Geroscience, 41, 383-393.

[2] Baier, M. P., Nagaraja, R. Y., Yarbrough, H. P., Owen, D. B., Masingale, A. M., Ranjit, R., … & Logan, S. (2022). Selective ablation of Sod2 in astrocytes induces sex-specific effects on cognitive function, d-serine availability, and astrogliosis. Journal of Neuroscience, 42(31), 5992-6006.

[3] Logan, S., Baier, M. P., Owen, D. B., Peasari, J., Jones, K. L., Ranjit, R., … & Sonntag, W. E. (2023). Cognitive heterogeneity reveals molecular signatures of age-related impairment. PNAS nexus, 2(4), pgad101.

[4] Sochocka, M., Diniz, B. S., & Leszek, J. (2017). Inflammatory response in the CNS: friend or foe?. Molecular neurobiology, 54, 8071-8089.

[5] Ogrodnik, M., Evans, S. A., Fielder, E., Victorelli, S., Kruger, P., Salmonowicz, H., … & Jurk, D. (2021). Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice. Aging cell, 20(2), e13296.

Date Posted: March 12, 2025

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Human Exposome Project Explores Environmental Disease Causes

Recent research confirms the relatively minor role that genetics plays in our health, with the ‘exposome’, defined as the totality of exposures individuals experience over their lives affecting their health, responsible for 10 times more variation in mortality risk than genetic predisposition [1].

A paper published in Nature Medicine today, ‘Cities, communities and clinics can be testbeds for human exposome and aging research’ [2], sets out ways to start measuring how humans are affected by the exposome and furnish long-overdue evidence to design environments that enhance healthy life expectancy while reducing health and wellbeing inequalities.

The publication of the paper coincides with a tipping point for an international movement behind the ‘Human Exposome Project’, a generation on from the Human Genome Project, to understand how external exposures (including social, behavioural and geo-physical factors) and their interaction with internal factors (such as genetics and physiology), affect an individual’s health and overall resilience.

The Exposome Moonshot Forum is meeting for the first time in Washington, DC, 12-15 May 2025, to launch an unprecedented international scientific endeavour to map the combined impact of environmental factors that impact human health from conception to death.

Specific environmental factors can activate pathological pathways that contribute to disease and accelerate aging. The ability to capture, analyse and link individual data outside the medical record can show how external exposures affect a person’s health across their lifetime. These interactions can now be much better understood at an individual level and traced with unprecedented precision using artificial intelligence, representing a significant leap forward in determining the impact of the exposome at an aggregated, population health level.

This work is crucial to define new ways to address the chronic disease epidemic and ageing demographic now creating an economic drag in many nations around the world. The evidence will shape more effective public health interventions urgently needed to shift investment and policy away from an unsustainable healthcare model to one more rooted in prevention.

Tina Woods, steering committee member, Exposome Moonshot Forum; CEO, Collider Health; executive director of the International Institute of Longevity, and corresponding author says: ‘The time for the Human Exposome Project has come and I am excited to be participate in the Exposome Moonshot Forum to move it from concept to reality. We need to measure the exposome to demonstrate the return on investing in health and incentivising prevention.’

Professor David Furman, Buck Institute for Research on Aging, director of the Stanford 1000 Immunomes Project, steering committee member, Exposome Moonshot Forum, and corresponding author says: ‘At a time of increasing environmental threats to human health such as air pollution and microplastics, we have the technologies like applied artificial intelligence to help us to unravel the complex interactions between environment, immunity and health at an individual level that can be aggregated up to get a true picture of the relative impact drivers of population health’.

Professor Nic Palmarini, director of the National Innovation Centre for Ageing, and author, says: ‘We have the technologies and tools to understand the human exposome with clinics, communities and cities acting as ideal real-world testbeds to understand what solutions will promote healthier behaviours and ultimately, outcomes.’

Buck Institute

The mission of the Buck Institute is to end the threat of age-related disease for this and future generations. It is the first biomedical research institution devoted solely to research on ageing revolving around our commitment to helping people live better longer.

Media contact:

Kris Rebillot, Senior Director of Communications

415-209-2080

krebillot@buckinstitute.org

National Innovation Centre for Ageing

The UK’s National Innovation Centre for Ageing is a world-leading organisation to help co-develop and bring to market products and services which create a world in which we people live better, for longer.

Media contact:

Lynne Corner

+44 (0) 7713 245780

lynne.corner@ncl.ac.uk

International Institute for Longevity

The International Institute of Longevity (IIOL) is focused on driving global excellence, industry standards and best practice in the real-world application of longevity science into ‘longevity clinics’ as well as scientific and medical innovation to extend human healthspan, resilience and flourishing in the wider context of corporate and urban health and wellness.

Media contact:

Tina Woods

+44 (0) 7808 402032

t.woods@l-institute.com

Exposome Moonshot Forum

The Exposome Moonshot Forum on 12-15 May in Washington DC is intended to define and accelerate the future of the Human Exposome Project (HEP). The central aim of the Forum is to identify the resources, policies, and collaboration necessary to drive the successful implementation of the HEP, ensuring longevity and impact. Outcomes will centre around:

Defining clear, actionable steps toward the scalable implementation of the HEP.
Building consensus on the essential policy changes needed to support and expand research.
Establishing long-term collaborative partnerships that will bring together diverse sectors, including academia, industry, government agencies, and non-profit organizations, and divert critical funds toward this project and toward successful integration of active working groups

Media contact:

Eliza Cole, Communications Specialist

ecole28@jh.edu

Yes I will donate❤️

Literature

[1] Argentieri, M.A., Amin, N., Nevado-Holgado, A.J. et al. Integrating the environmental and genetic architectures of aging and mortality. Nat Med (2025). [2] Woods, T., Furman D., Palmarini N. et al. Cities, communities and clinics can be testbeds for human exposome and aging research. Nat Med (2025).

Date Posted: March 12, 2025

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How Life Expectancy Has Changed in Europe

A recent country-level analysis of life expectancy among several European nations shows changes in life expectancy trends and how well-designed national policies can reduce or minimize exposure to risk factors, thus improving life expectancy [1].

Slowdown in life expectancy increase

Life expectancy has grown in high-income countries since at least 1900, except during the two World Wars and the 1918 influenza pandemic [2]. However, the speed of the growth differed; for example, since 2011, Europe’s trend towards life expectancy increases was reduced, and this was followed by a decline in life expectancy in most European countries due to the COVID-19 pandemic [3, 4].

The authors of this recent study used the data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 to compare changes in life expectancy and exposure to risk factors in the 16 founding European Economic Area countries and four UK nations.

The life expectancy at birth was defined as “the mean number of years that a newborn infant could expect to live, if he or she were to pass through life exposed to the sex-specific and age-specific death rates prevailing at the time of his or her birth, in a given country.”

They compared periods of 1990 to 2011 (pre-slowdown in life expectancy), 2011 to 2019 (slowdown in life expectancy to pre-COVID-19 pandemic), and 2019 to 2021 (COVID-19 pandemic).

Country-level analysis

When analyzed separately, all countries showed improved life expectancy from 1990 to 2011 and 2011 to 2019; however, the rate varied. Confirming the observations of bulk data analysis reported previously, the rate of life expectancy improvement was higher in the 1990-to-2011 period than the 2011-to-2019 period.

Norway was the only exception from that observation. In Norway, the trend of life expectancy increased more during the 2011-to-2019 period compared to the 1990-to-2011 period.

During the COVID-19 pandemic and post-pandemic period, all countries but Ireland, Iceland, Sweden, Norway, Denmark, and Belgium experienced an absolute fall in life expectancy, with Greece and England observing the most significant decrease.

Cardiovascular diseases, cancers, and COVID-19

The life expectancy improvements seen in the 1990-to-2011 period stem from improvements related to causes of death attributed to cardiovascular diseases and neoplasms, which are tissue masses that result from abnormal growth, whether benign or cancerous.

Unsurprisingly, the decrease in life expectancy in years 2019–21 can be attributed to the deaths from respiratory infections and other COVID-19-related health problems. However, before the COVID-19 pandemic period, reductions in improvements in life expectancy were primarily driven by cardiovascular diseases.

The researchers also made an interesting observation: “among the studied countries, those with the greatest slowdown in life expectancy improvements before the COVID-19 pandemic were generally most severely affected by COVID-19 and had some of the largest decreases in life expectancy in 2019-21.”

Avoiding risk

The researchers analyzed risk factors, attributed to different causes of death, for both sexes in all countries combined in 2019. The top three risk factors for cardiovascular disease were high systolic blood pressure, dietary risks, and high LDL cholesterol. For neoplasms, the top risk factors included tobacco smoke, dietary risks, and occupational risks.

The levels of different risk factors changed with time, such as exposure to tobacco smoke; even though it is still a high population risk, it has decreased over time. On the other hand, BMI has increased in all countries, and dietary risks, high alcohol use, and low physical activity remain high in most.

The authors also point to high LDL cholesterol and systolic blood pressure, which declined until before 2011; however, this trend reversed after 2011 in many countries.

The danger of a risk factor varies by the time between exposure to it and the start of the disease that it causes, the length of exposure, and its interactions with other risk factors. Unfortunately, this dataset doesn’t provide some of that information.

Funding healthcare

Following their analysis, the authors discuss governmental policies and their impact on life expectancy. For example, they mention national fiscal and healthcare policies that impact the population’s life expectancy, especially for people in the worst socioeconomic situations.

An example of policies aimed at increase access to healthcare are Belgian, French, and Norwegian national policies, which, in recent years, have focused on increasing cancer diagnosis and treatment. The authors hold that these policies improved life expectancy related to neoplasms between 1990 and 2019. Additionally, some research has suggested that funding cuts to health, social care, and welfare since 2010 contributed to the slowdown in life expectancy improvement [5, 6].

Diet and physical activity are the foundation of health and longevity

Diagnosis and treatment happen after a person suffers from a disease. Preventing diseases from occurring through proper diet and physical activity might be more effective at increasing life expectancy.

The authors give examples of how healthy food consumption can be influenced by effective policy. An example is Norway, which had implemented a sugar tax as early as 1922. Similarly, starting in the 1980s, the Norwegian government talked with the industry about reducing the amount of salt in food products. This was complemented by Norway’s ‘Action Plan on Nutrition 2007–2011’, which, apart from education, also focused on other nutritional aspects, such as increasing focus on nutrition in a health care setting.

This broader approach has proven more effective than focusing only on education and voluntary dietary changes. Apart from diet, physical activity is the cornerstone of health and reducing premature mortality. Unfortunately, accordingly to this analysis, at the population level, there were no improvements in the levels of even low physical activity across the studied countries. The authors believe that systematic strategies and incentives are necessary to change that.

Ultimately, the authors intend for policymakers to utilize this analysis as a guide to reverse their countries’ slowdown in life expectancy improvement. They also hold that countries that implement successful policies can be used as examples for others to follow.

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Literature

[1] GBD 2021 Europe Life Expectancy Collaborators (2025). Changing life expectancy in European countries 1990-2021: a subanalysis of causes and risk factors from the Global Burden of Disease Study 2021. The Lancet. Public health, 10(3), e172–e188.

[2] Roser M. (2020) The Spanish flu: the global impact of the largest influenza pandemic in history.

[3] Raleigh VS. (2019) Trends in life expectancy in EU and other OECD countries. OECD Health Working Papers 108.

[4] Organisation for Economic Co-operation and Development, EU. (2018) Health at a glance: Europe 2018: state of health in the EU Cycle.

[5] Alexiou, A., Fahy, K., Mason, K., Bennett, D., Brown, H., Bambra, C., Taylor-Robinson, D., & Barr, B. (2021). Local government funding and life expectancy in England: a longitudinal ecological study. The Lancet. Public health, 6(9), e641–e647.

[6] McCartney, G., McMaster, R., Popham, F., Dundas, R., & Walsh, D. (2022). Is austerity a cause of slower improvements in mortality in high-income countries? A panel analysis. Social science & medicine (1982), 313, 115397.

Date Posted: March 11, 2025

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A New Study Claims to Challenge Peto’s Paradox

Applying statistical methods to a large dataset spanning almost 300 species, scientists found a positive correlation between body size and cancer prevalence [1]. Other researchers dispute that these findings invalidate the famous paradox.

A paradox of size

Cancer has forever been a mortal enemy of multicellular life. Sometimes, the cell’s “program” malfunctions, causing it to divide uncontrollably, until its progeny takes over the organism and kills it. This can happen to almost any cell, and one cell is enough.

A logical conclusion is that the more cells an animal has, the greater its risk of developing cancer. Hence, larger animals with many times more cells should be getting cancer much more frequently, but this does not appear to occur in nature. Instead, lifespan is positively correlated with body size (barring a few outliers), and small animals often get more cancer, not less. For instance, cancer is a highly prevalent cause of death in lab mice.

This became known as Peto’s paradox, after Sir Richard Peto, a British epidemiologist and statistician, who first articulated the idea in 1977 while studying cancer risks in different species. Of course, there’s nothing mystical about it: many large, long-lived species have developed superior anti-cancer defenses, such as DNA repair mechanisms, robust immune systems, and enhanced methods of removing cancerous cells through apoptosis. A lower cell division rate in some large species might also explain a part of the paradox.

For example, elephants have at least 20 copies of the TP53 gene, which plays crucial roles in detecting and repairing DNA damage and in triggering cell death in potentially cancerous cells, while humans have just one. Studying those mechanisms is a rapidly growing field in geroscience.

The correlation between body size and cancer

Since Peto’s original observation, several studies have investigated this question. Some of them found no correlation between cancer prevalence and body sizes, seemingly confirming the paradox [2]. However, those earlier studies were plagued by low data availability; after all, it’s hard to amass enough necropsies for multiple species.

Enter this new paper by scientists from the University of Reading, University College London and the Johns Hopkins University School of Medicine. This paper was published in Proceedings of the National Academy of Sciences (PNAS) and ambitiously titled “No evidence for Peto’s paradox in terrestrial vertebrates.”

The paper is based on a dataset created for a slightly earlier study by Compton et al. [3] The unprecedentedly large dataset consists of 16,049 necropsy records for 292 species, which made better statistical analysis possible. Interestingly, that paper did not reach the same definitive conclusion but instead highlighted “limitations to Peto’s paradox, by showing that large animals do tend to get somewhat more neoplasms and malignancies when compared with smaller animals.”

The authors of the PNAS paper claim to have applied more robust statistical analysis to the same dataset, which allowed them to extract a clearer signal. Professor Chris Venditti, senior author of the research at the University of Reading, said, “Everyone knows the myth that elephants are afraid of mice, but when it comes to cancer risk, mice are the ones who have less to fear. We’ve shown that larger species like elephants do face higher cancer rates—exactly what you’d expect given they have so many more cells that could go wrong.”

The researchers separately analyzed birds and mammals, which stop growing at certain points in their life, along with amphibians and reptiles, many of which never do. In the first subset, the authors controlled for body mass, while in the second, for body length (which itself might have affected the results). They also controlled for species’ longevity, although the longevity data was limited.

They found a significant positive association between neoplasia (this included both benign and malignant tumors, which were strongly correlated) and body size. For mammals, the relationship was β = 0.129, indicating a relatively flat slope (a linear relationship would have β = 1). In amphibians and reptiles, the correlation was stronger: β = 0.433. “Across all four vertebrate classes, larger species have an increased prevalence of malignancy compared to smaller species, thus demonstrating no evidence of Peto’s paradox,” the paper concludes.

The paradox is dead, long live the paradox

However, this suggests a narrow reading of Peto’s paradox as nothing short of zero positive correlation between cancer and body size. “The conclusion of this paper is not supported by the results,” said Dr. Vera Gorbunova of the university of Rochester, a researcher of long-lived species who was not involved in this study. “Even if there is a small statistical trend towards increased cancer with increased body size, it is not proportional to the number of cells or cell divisions experienced by larger species. An elephant still has much lower cancer incidence than a mouse. The authors themselves conclude that larger species have evolved better control of the cell cycle. This means they did evolve additional anticancer defenses, which is what Peto’s paradox posits.”

Indeed, the authors point to some instances of animals clearly “outsmarting” cancer, with elephants having 56% lower cancer rates than the researchers’ model expected for their body size, and naked mole rats, rodents famous for their longevity, performing even stronger. On the opposite side of the spectrum lie the notoriously cancer-prone ferrets and opossums. Interestingly, bats and turtles, highlighted in Compton et al. as supporting Peto’s paradox, are not mentioned in this new study.

Dr. Joanna Baker, co-author from the University of Reading, said, “When species needed to grow larger, they also evolved remarkable defenses against cancer. Elephants shouldn’t fear their size—they developed sophisticated biological tools to keep cancer in check. It’s a beautiful example of how evolution finds solutions to complex challenges.”

An important aspect of this study is that the researchers were able to count in some evolutionary differences. In particular, they found that species that evolved larger body sizes more rapidly, such as through a series of evolutionary ‘bursts’, were more likely to have stronger anti-cancer defenses.

“These studies represent a more comprehensive quantitative evaluation of some of the theories of evolution of aging and life history strategies,” said Dr. Emma Teeling of the University College Dublin, who also was not involved in this study. “Collecting these malignancy and life history studies requires decades if not centuries for long-lived species. This is why these studies are confined to captive species, where perhaps what was measured is actually the potential stress of captivity rather than true rate of malignancy. We are limited to species that we are able to maintain in captivity, which are not necessarily those that have evolved the most robust and therefore the most interesting anti-cancer mechanisms.”

“The authors detected a signal of evolution in action, where indeed with increased body size, there is a trend towards increased cancer incidence that then gets compensated by evolution of additional tumor suppressor mechanisms,” Gorbunova said. “Overall, I think the title of the paper is somewhat ‘sensationalized’. If this study found that upon certain phylogenetic comparisons larger species have slightly increased cancer risk, it does not eliminate Peto’s paradox.”

“The outliers in both of these studies, the species that were observed to have more or less than predicted cancer regardless of the methods used, are the most interesting candidates,” Teeling added. “Some of these species have been the focus of previous anti-aging research, such as the naked mole rat. Both studies will stimulate new ways to consider the evolution of cancer and anti-cancer mechanisms across the tree of life, new methods, datasets, and conclusions.”

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Literature

[1] Butler, G., Baker, J., Amend, S. R., Pienta, K. J., & Venditti, C. (2025). No evidence for Peto’s paradox in terrestrial vertebrates. Proceedings of the National Academy of Sciences, 122(9), e2422861122.

[2] Boddy, A. M., Abegglen, L. M., Pessier, A. P., Aktipis, A., Schiffman, J. D., Maley, C. C., & Witte, C. (2020). Lifetime cancer prevalence and life history traits in mammals. Evolution, medicine, and public health, 2020(1), 187-195.

[3] Compton, Z. T., Mellon, W., Harris, V. K., Rupp, S., Mallo, D., Kapsetaki, S. E., … & Boddy, A. M. (2025). Cancer prevalence across vertebrates. Cancer discovery, 15(1), 227-244.

Date Posted: March 10, 2025

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An Existing Diabetes Drug May Treat Aspects of Aging

In the Nature publication Signal Transduction and Targeted Therapy, researchers have described how glibenclamide, a drug used to treat type 2 diabetes, partially reverses epigenetic alterations and fights cellular senescence in mice.

A system tightly tied together

This paper begins with a discussion of the relationship between epigenetic alterations and cellular senescence. The histone H3K4me3 upregulates the senescence-related genes Cdkn1a, which is responsible for the biomarker p21 [1], and Cdkn2a, which is responsible for the biomarker p16 [2]. H3K27me3, on the other hand, downregulates these genes. Another histone, H3K9me3, suppresses repetitive genetic elements that cause an inflammatory response related to senescence [3].

While research has been done on directly targeting these histones [4], doing this with small molecules is difficult because they are structurally similar [3]. These researchers point to evidence suggesting that it may be more effective to target metabolism instead, as fundamental aspects of metabolism are linked to histone methylation [5].

These researchers had previously found that chlorpropamide provides a rejuvenation effect in C. elegans worms through a mitochondrial pathway [6]. They began this work to more definitively determine how and why this was happening, looking for a therapeutic target.

A metabolic target

This work began with a study on lung fibroblasts. Using a chemical probe based on chlorpropamide, the researchers looked at protein functions in order to determine what was being affected by this compound. They found MDH2 to be a potential target, as it had similar mitochondrial effects as chlorpropamide.

Further work in lung fibroblasts found that MDH2 was directly related to cellular senescence, whether it was induced by doxycycline or by excessive replication. The researchers created two cell lines, one with suppressed MDH2 and the other with overexpressed MDH2, to determine whether this relationship was causative in nature. They found that suppressing MDH2 reduced key senescence biomarkers, including SA-β-gal and p16, while overexpressing it increased them. The difference was not large, but it was statistically significant.

The researchers then tested how MDH2 interacts with five different sulfonylureas, a class of drugs that includes chlorpropamide. Of these drugs, the researchers found that glibenclamide has the strongest interaction with MDH2, far stronger than that of chlorpropamide.

In doxycycline-induced senescent lung fibroblasts, glibenclamide was found to reduce senescence biomarkers, including SA-β-gal, p16, and interleukins. Its overall effects in this area seemed to be roughly on par with those of metformin, another diabetes drug; it was not as good at reducing the inflammatory cytokine IL-6, but it reduced IL-1β in these cells, which metformin did not do. These beneficial effects were confirmed to be dependent on MDH2, as glibenclamide had no effects in cells with silenced MDH2.

Increases in histones and ROS

While the effects on lifespan and frailty were positive, glibenclamide increased, rather than decreased, mitochondrial reactive oxygen species (ROS) in lung fibroblasts. The researchers found that this was due to the inhibition of the TCA metabolic cycle, which forced the mitochondria to use oxygen-burning glycolysis instead [7]. The researchers hold that these effects on the TCA cycle are core to its beneficial effects, as they relate to the methionine cycle, which affects methylation.

On the first day of treatment in lung fibroblasts, glibenclamide immediately upregulated the senescence suppressor H3K27me3. Interestingly, when given for five days, glibenclamide upregulated both H3K4me3 and H3K27me3 in these cells while having no effect on H3K9me3.

Benefits for mice

The researchers also experimented on Black 6 mice. One group of 12-month-old mice was given glibenclamide, another was given NMN, and a third served as a control group. At 26 and 27 months of age, the glibenclamide group had significantly less frailty than either of the other groups. Mice given NMN appeared to live slightly longer on average, but the effect was not statistically significant; mice given glibenclamide, on the other hand, lived significantly longer.

Another experiment found that, while its physical benefits were not apparent at this age, glibenclamide reduces liver fibrosis and senescence in 20.5-month-old mice. In these animals, the drug was found to have significant effects on H3K27me3 but not H3K4me3.

While its anti-aging effects have not been tested in human beings, glibenclamide is a drug that is already being prescribed in the clinic. If these beneficial effects can be confirmed in human beings, this drug might be more widely prescribed to slow cellular senescence, particularly in the liver. The researchers also suggest that derivatives of this drug could be developed to more precisely target MDH2 to further slow cellular senescence.

Yes I will donate❤️

Literature

[1] Yan, K., Ji, Q., Zhao, D., Li, M., Sun, X., Wang, Z., … & Liu, G. H. (2023). SGF29 nuclear condensates reinforce cellular aging. Cell Discovery, 9(1), 110.

[2] Kotake, Y., Zeng, Y., & Xiong, Y. (2009). DDB1-CUL4 and MLL1 mediate oncogene-induced p16 INK4a activation. Cancer research, 69(5), 1809-1814.

[3] Zhang, B., Long, Q., Wu, S., Xu, Q., Song, S., Han, L., … & Sun, Y. (2021). KDM4 orchestrates epigenomic remodeling of senescent cells and potentiates the senescence-associated secretory phenotype. Nature aging, 1(5), 454-472.

[4] Hsu, C. L., Lo, Y. C., & Kao, C. F. (2021). H3K4 methylation in aging and metabolism. Epigenomes, 5(2), 14.

[5] Salminen, A., Kauppinen, A., Hiltunen, M., & Kaarniranta, K. (2014). Krebs cycle intermediates regulate DNA and histone methylation: epigenetic impact on the aging process. Ageing research reviews, 16, 45-65.

[6] Mao, Z., Liu, W., Huang, Y., Sun, T., Bao, K., Feng, J., … & Li, J. (2022). Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species. Acta Pharmaceutica Sinica B, 12(2), 665-677.

[7] Li, X., Yang, Y., Zhang, B., Lin, X., Fu, X., An, Y., … & Yu, T. (2022). Lactate metabolism in human health and disease. Signal transduction and targeted therapy, 7(1), 305.

Date Posted: March 6, 2025

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A Klotho Gene Therapy Extends Life in Male Mice

In Molecular Therapy, a team of researchers has described how increasing the expression of a form of Klotho, a protein that has been frequently found to have rejuvenative effects, leads to longer lifespans in male mice.

Klotho has various forms

In their introduction, the researchers distinguish between the various forms of Klotho. The full mRNA sequence that generates Klotho creates two homologous effective sections (KL1 and KL2) and a membrane that is meant for transportation between cells: this full version is m-KL [1]. Once enzymes take away this membrane, however, it becomes p-KL, with each section being p-KL1 and p-KL2.

However, this full version interferes with the function of FGF23, a protein that manages the metabolism of minerals [2]. Artificially upregulating this protein, therefore, is not safe [3].

Another form of Klotho, secreted Klotho (s-KL), does not have this problem. s-KL has been found to have multiple anti-aging effects according to a review of 65 studies [4]. Of course, without the transmembrane protein, it is not fit for intercellular transportation. Therefore, the researchers used an adeno-associated virus (AAV) to deliver a gene therapy that upregulates Klotho in the mice in this experiment.

Improvements in lifespan

The researchers used a total of 96 mice of the Black 6 strain: a group that received the AAV at 6 months, a group that received the AAV at 12 months, and a control group that received an ineffective AAV at 6 months. Both male and female mice were included in this experiment.

The treatment had far different effects in males and females. In female mice, the treatment had similar effects at 6 months and 12 months, but the increase in s-KL was accompanied by serious health problems during the course of the experiment, including skin ulcers and bleeding from the anus. In male mice, the AAV upregulated s-KL much more than in female mice, and it was much more effective at 12 months than at 6 months. Despite having far more s-KL, the males did not experience any of the health problems that the females did; instead, they received significant improvements to their lifespan.

Improvements to tissues and performance

Interestingly, at the age of 24 months, females showed improvements on the rotarod balance test that males did not. Both sexes given the s-KL AAV at 12 months were able to hold onto a horizontal bar longer than their control groups. In a three-trial grip strength test, the AAV-treated males performed far better, while the females performed better during only the first trial. The males also had significant reductions in fibrosis.

Regeneration capability was tested by transplanting muscles from old mice into younger mice. The muscle fibers in the AAV-treated animals became much larger than those from the control group. Muscles derived from the animals treated at 6 months old grew a wider variety of fiber sizes than those derived from animals treated at 12 months. Proliferation markers, and markers relating to a muscle-related fate of stem cells, were increased in the muscles derived from the mice that had received the s-KL AAV.

The researchers also tested bone tissue, seeing significant improvements to bone structure in females treated at 6 months and non-significant improvements in males treated at 12 months. Curiously, while FGF23 was upregulated along with many other bone-related factors in male mice, it was downregulated in female mice. This may be beneficial for females, as age-related increases in FGF23 have been linked to osteoporosis [5].

While no behavior testing was done in this study, the researchers did examine the mice’s brains. They found that, in the treated animals, there were more functional neurons and a thicker cellular layer, and markers of cellular proliferation were increased in the hippocampus. An examination of differently expressed genes revealed that the treated animals had fewer age-related changes than the control group.

The researchers note that this is the first time an AAV for s-KL has demonstrated lifespan increases in wild-type mice; previous experiments used transgenic mice. They believe that further experiments should test mice with different genetic backgrounds, because the side effects they saw in this experiment may or may not be limited to the AAV’s effects on Black 6 mice. Further work may elucidate exactly why klotho treatment has such different effects on males and females.

Yes I will donate❤️

Literature

[1] Chen, C. D., Tung, T. Y., Liang, J., Zeldich, E., Tucker Zhou, T. B., Turk, B. E., & Abraham, C. R. (2014). Identification of cleavage sites leading to the shed form of the anti-aging protein klotho. Biochemistry, 53(34), 5579-5587.

[2] Kurosu, H., Ogawa, Y., Miyoshi, M., Yamamoto, M., Nandi, A., Rosenblatt, K. P., … & Kuro-o, M. (2006). Regulation of fibroblast growth factor-23 signaling by klotho. Journal of Biological Chemistry, 281(10), 6120-6123.

[3] Roig-Soriano, J., Sánchez-de-Diego, C., Esandi-Jauregui, J., Verdés, S., Abraham, C. R., Bosch, A., … & Chillón, M. (2023). Differential toxicity profile of secreted and processed α-Klotho expression over mineral metabolism and bone microstructure. Scientific reports, 13(1), 4211.

[4] Abraham, C. R., & Li, A. (2022). Aging-suppressor Klotho: Prospects in diagnostics and therapeutics. Ageing Research Reviews, 82, 101766.

[5] Sirikul, W., Siri-Angkul, N., Chattipakorn, N., & Chattipakorn, S. C. (2022). Fibroblast growth factor 23 and osteoporosis: evidence from bench to bedside. International Journal of Molecular Sciences, 23(5), 2500.

Date Posted: March 5, 2025

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Ginkgolide B Improves Healthspan and Lifespan in Female Mice

The authors of a recent study describe Ginkgolide B, a compound with senotherapeutic potential that improved muscle health, metabolism, frailty, inflammation, and senescence metrics and increased lifespan in female mice [1].

From East Asia to the clinic

Ginkgolide B is a compound that can be extracted from Ginkgo biloba, an East Asian tree known as the maidenhair tree. Previous research indicates that Ginkgolide B may offer many health benefits, such as improvements in osteoporosis and muscle regeneration in aged mice [2-7].

Therefore, these researchers hold that Ginkgolide B’s good safety, tolerability, and pharmacokinetic profile in humans [8, 9] and promising beneficial effects seen in model organisms make it a good candidate for healthspan and lifespan studies.

Extending lifespan

The researchers tested Ginkgolide B’s impact on female mouse lifespan. They started Ginkgolide B administration at 20 months (equivalent to 70- to 80-year-old humans). Ginkgolide B significantly extended the median lifespan by 8.5% and “extended the mean maximal lifespans of the 10% and 20% longest-lived mice by approximately 55” days.

Additionally, the researchers observed a reduced incidence of tumors; however, even the Ginkgolide B-treated mice with tumors still had longer lives, suggesting that Ginkgolide B extends lifespan not only by reducing tumors but through its beneficial impact on multiple organs and molecular processes.

Strengthening muscle

Apart from increasing lifespan, an increase in healthspan was also observed.

First, the researchers tested the impact of Ginkgolide B on muscle mass and strength. Ginkgolide B treatment improved female mice’s muscle strength, exercise capacity, and balance. It also reversed aging-related muscle wasting symptoms, such as a decreased skeletal muscle-to-body ratio, alterations to protein content in muscle, and muscle atrophy markers in aged skeletal muscle. Ginkgolide B also led to enlargement in the thigh’s main (femoral) artery and capillary density, which allowed for increased accessibility of oxygen and nutrients in muscles. However, it didn’t improve fatigue resistance or muscle recovery rate.

On the molecular level, Ginkgolide B treatment reversed several age-related changes associated with declining physical performance and muscle contraction; for example, it reduced aging-related increases in intramuscular lipid infiltration and collagen deposition.

Since the researchers focused on female mice, they also investigated sex hormones’ role in age-dependent muscle functioning. They surgically removed the mice’s ovaries, resulting in estrogen-deficient mice. Loss of estrogen led to muscle deterioration and decreased physical performance. Ginkgolide B treatment restored those functions in a dose-dependent manner, with high doses of Ginkgolide B almost completely restoring measured muscle functions.

Improved aging markers

Apart from declining muscular health, aging results in changes to metabolism, increased frailty, the chronic, low-grade inflammation known as inflammaging, and declining organ health. Ginkgolide B treatment helped alleviate those symptoms, such as by reducing the frailty index by 64.8% and benefiting the heart, kidney, spleen, and liver.

After two months of Ginkgolide B treatment, the body composition of aged mice resembled that of young mice. Similarly, it reversed disruption in biochemical measurements, such as serum triglyceride and total cholesterol levels, in aged mice and improved glucose tolerance and disruptions in glucose metabolism-related genes in skeletal muscle and liver.

Treatment with Ginkgolide B also positively impacted the inflammatory profile of aged mice, making it similar to that of young mice. The researchers also observed changes in the profiles of immune cells in aged mice, such as decreases in pro-inflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages.

Inflammaging, among other aging-related processes, is linked to senescent cells. The researchers observed that Ginkgolide B treatment positively impacted the expression of several senescence-associated markers, such as the senescence-associated secretory phenotype (SASP) along with DNA damage, cell cycle, cell size, and cell proliferation in different organs and in cell culture models of induced senescence.

Molecular pathways

The authors of this study also examined aging-induced molecular changes by conducting multiple analyses of gene expression in the mouse leg muscle using either bulk expression data or expression data from single nuclei.

The results indicated that both aging and Ginkgolide B impacted gene expression. Ginkgolide B treatment had slight but measurable impacts in this area, partially reversing some of the changes that are brought about by normal aging in mice.

An analysis that focused on the hallmarks of aging showed that multiple genes related to these hallmarks are disrupted during normal aging. Ginkgolide B “partially restored intercellular communication, cellular senescence, nutrient sensing deregulation and mitochondrial dysfunction.”

Further gene expression analysis was performed separately for different subtypes of nuclei. The authors observed that one of the subtypes, called Runx1+ type 2B myonuclei, which appear in muscle cells, had the most significant alterations to gene expression. They refer to this subtype of cells as having a “host of age-related and GB-rescued signatures at the single-nucleus level.”

These myonuclei were enriched with apoptosis and ROS markers during aging, which were reversed by Ginkgolide B treatment. The authors hypothesize that the enrichment of apoptosis markers suggests that age-related apoptosis in Runx1+ type 2B myonuclei contributes to muscle degeneration.

The authors conducted further database searches and experiments to find a molecular pathway linking Ginkgolide B treatment and Runx1, a transcription factor that controls the expression of multiple genes. They identified miR-27b-3p, a microRNA whose levels are decreased in aged muscles and restored by Ginkgolide B treatment. Restoration of miR-27b-3p levels leads to reduced expression of Runx1.

Senotherapeutic potential

The researchers concluded that Ginkgolide B has a strong senotherapeutic potential, even when started late in life, and can help address aging-related conditions that current senotherapeutics fail to address, such as sarcopenia. However, the obtained results should be investigated in different mouse strains and eventually in humans to confirm their therapeutic value.

Yes I will donate❤️

Literature

[1] Lee, C. W., Wang, B. Y., Wong, S. H., Chen, Y. F., Cao, Q., Hsiao, A. W., Fung, S. H., Chen, Y. F., Wu, H. H., Cheng, P. Y., Chou, Z. H., Lee, W. Y., Tsui, S. K. W., & Lee, O. K. (2025). Ginkgolide B increases healthspan and lifespan of female mice. Nature aging, 5(2), 237–258.

[2] Wu, T., Fang, X., Xu, J., Jiang, Y., Cao, F., & Zhao, L. (2020). Synergistic Effects of Ginkgolide B and Protocatechuic Acid on the Treatment of Parkinson’s Disease. Molecules (Basel, Switzerland), 25(17), 3976.

[3] Zhao, Y., Xiong, S., Liu, P., Liu, W., Wang, Q., Liu, Y., Tan, H., Chen, X., Shi, X., Wang, Q., & Chen, T. (2020). Polymeric Nanoparticles-Based Brain Delivery with Improved Therapeutic Efficacy of Ginkgolide B in Parkinson’s Disease. International journal of nanomedicine, 15, 10453–10467.

[4] Yao Y. (2020). Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet‑induced obese mice via endoplasmic reticulum stress and p‑STAT3/STAT3 signaling. Molecular medicine reports, 21(3), 1059–1070.

[5] Zhu, B., Xue, F., Zhang, C., & Li, G. (2019). Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way. Journal of cellular and molecular medicine, 23(8), 5782–5793.

[6] Lee, C. W., Lin, H. C., Wang, B. Y., Wang, A. Y., Shin, R. L., Cheung, S. Y. L., & Lee, O. K. (2021). Ginkgolide B monotherapy reverses osteoporosis by regulating oxidative stress-mediated bone homeostasis. Free radical biology & medicine, 168, 234–246.

[7] Wang, B. Y., Chen, Y. F., Hsiao, A. W., Chen, W. J., Lee, C. W., & Lee, O. K. (2023). Ginkgolide B facilitates muscle regeneration via rejuvenating osteocalcin-mediated bone-to-muscle modulation in aged mice. Journal of cachexia, sarcopenia and muscle, 14(3), 1349–1364.

[8] Shen, C., Jin, X., Wu, M., Huang, X., Li, J., Huang, H., Li, F., Liu, J., Rong, G., & Song, S. (2020). A sensitive LC-MS/MS method to determine ginkgolide B in human plasma and urine: application in a pharmacokinetics and excretion study of healthy Chinese subjects. Xenobiotica; the fate of foreign compounds in biological systems, 50(3), 323–331.

[9] Shao, F., Zhang, H., Xie, L., Chen, J., Zhou, S., Zhang, J., Lv, J., Hao, W., Ma, Y., Liu, Y., Ou, N., & Xiao, W. (2017). Pharmacokinetics of ginkgolides A, B and K after single and multiple intravenous infusions and their interactions with midazolam in healthy Chinese male subjects. European journal of clinical pharmacology, 73(5), 537–546.

Date Posted: March 4, 2025

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Genes Affect Aging and Mortality Less Than Extrinsic Factors

A massive study from the University of Oxford has evaluated the relative impact of genetic and non-genetic factors on aging, mortality, and disease prevalence.

A deeper dive

The question of how strongly genes affect our longevity has been asked before, and the emerging answer is not very much [1]. Most of the variation in human lifespan seems to come from extrinsic factors, such as smoking and physical activity. However, quantifying the correlation between these myriad factors and longevity is tricky. In this new study coming from the University of Oxford and published in Nature Medicine, the researchers use the trove of data accumulated in the UK Biobank (UKB), a unique repository of various health data on hundreds of thousands of British citizens, to bring us closer to the answer.

The authors sought to quantify the relative contributions of environmental factors (the exposome) versus genetics in determining aging, disease risk, and premature mortality. “A strong argument that nongenetic environmental factors play a key role in aging and premature mortality,” the paper says, “comes from the observation that global human lifespan has increased nearly twofold during the past 200 years, while the human genome is expected to have been stable in such a short period.”

The exposome and mortality

The researchers started with a list of 164 environmental exposures recorded in the UKB. They conducted an exposome-wide analysis to identify environmental exposures (in this term’s broadest sense) associated with all-cause mortality and employed various methods of addressing causality and confounding. For instance, some factors, such as household income and the number of cars owned, are interconnected and had to be disentangled using statistical models. These associations were validated in independent replication and validation cohorts.

Most factors associated with mortality were modifiable (such as physical activity) rather than non-modifiable (such as ethnicity). Smoking predictably ended up on top of the list of detrimental factors, along with the frequency of feeling tired and various measures of deprivation, such as renting a home from the local council versus owning one.

On the opposite side, some of the most beneficial factors included high household income, being employed and educated, physical activity, and living with a partner as opposed to living alone. Each of those factors was associated with a hazard ratio of less than 0.8, meaning a 20% or more reduction in mortality risk.

Cornelia van Duijn, St Cross Professor of Epidemiology at Oxford Population Health and senior author of the paper, said, “Our research demonstrates the profound health impact of exposures that can be changed either by individuals or through policies to improve socioeconomic conditions, reduce smoking, or promote physical activity.”

Interestingly, being of any ethnic background other than White (Asian, Black, mixed, or other ethnicity) was also strongly associated with less mortality risk. This correlation has been confirmed for the UK by previous research [2] and stands in stark contrast with the US, where being Black is associated with a shorter lifespan. The possible reasons for this discrepancy include differences in the two healthcare systems, cultural factors such as diet, and self-selection (“the healthy immigrant effect”), as most non-White people in the UK are immigrants.

Connection to aging and diseases

The researchers were also able to tie these exposures to biological aging via the proteomic aging clock that they developed in an earlier study [3]. The clock has been shown to be associated with mortality, major chronic age-related diseases, multimorbidity, and aging-related phenotypes, including frailty and cognitive function.

Each exposure that was associated with both mortality and proteomic aging (in the same direction) was also linked to concurrent incidence of multiple age-related diseases, “indicating that the exposome is a potential catalyst of disease multimorbidity,” the paper says. Smoking (both current status and pack-years for former smokers) was associated with 21 out of 25 diseases included in the analysis, while household income, Townsend deprivation index, home ownership, and frequency of feeling tired were associated with 19 diseases. In other words, age-related diseases rarely come alone, and many environmental factors drive numerous diseases simultaneously.

“Studies on environmental health have tended to focus on individual exposures based on a specific hypothesis,” van Duijn said. “While this approach has seen many successes, the method has not always yielded reproducible and reliable findings. Instead, we have followed a ‘hypothesis free’ exposome approach and studied all available exposures to find the major drivers of disease and death.”

Genes are less important (exceptions apply)

While some diseases are caused by single-gene variants, most do not have such a clear genetic connection and are instead associated with polygenic risk scores. The researchers analyzed these scores for 22 major diseases to find that, on average, they were much less associated with mortality and aging than the exposome.

Most of the variation in mortality was explained by age and sex (with women having lower mortality risk). Genetics only explained less than 2% of additional variation, whereas the exposome explained an additional 17%.

While this was the case for most outcomes, there were some notable outliers. Polygenic risk explained more variation than the exposome in the incidence of dementias along with breast, prostate, and colorectal cancer. The exposome, on the other hand, was much more predictive of lung, heart, and liver diseases.

“While genes play a key role in brain conditions and some cancers, our findings highlight opportunities to mitigate the risks of chronic diseases of the lung, heart and liver which are leading causes of disability and death globally,” van Duijn said. “The early life exposures are particularly important as they show that environmental factors accelerate ageing early in life but leave ample opportunity to prevent long-lasting diseases and early death.”

Dr. Austin Argentieri, lead author of the study at Oxford Population Health and Research Fellow at Massachusetts General Hospital, said, “Our exposome approach allowed us to quantify the relative contributions of the environment and genetics to ageing, providing the most comprehensive overview to date of the environmental and lifestyle factors driving ageing and premature death. These findings underscore the potential benefits of focusing interventions on our environments, socioeconomic contexts, and behaviors for the prevention of many age-related diseases and premature death.”

Professor Bryan Williams, Chief Scientific and Medical Officer at the British Heart Foundation, added, “Your income, postcode and background shouldn’t determine your chances of living a long and healthy life. But this pioneering study reinforces that this is the reality for far too many people.”

Yes I will donate❤️

Literature

[1] Ruby, J. G., Wright, K. M., Rand, K. A., Kermany, A., Noto, K., Curtis, D., … & Ball, C. (2018). Estimates of the heritability of human longevity are substantially inflated due to assortative mating. Genetics, 210(3), 1109-1124.

[2] White, C. (2021). Ethnic differences in life expectancy and mortality from selected causes in England and Wales: 2011 to 2014. Office for National Statistics.

[3] Argentieri, M. A., Xiao, S., Bennett, D., Winchester, L., Nevado-Holgado, A. J., Ghose, U., … & van Duijn, C. M. (2024). Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations. Nature medicine, 30(9), 2450-2460.

Date Posted: March 3, 2025

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Event Announcement: Longevity Science Summit

The Longevity Science Foundation (LSF) is thrilled to announce that it is organizing the Longevity Science Summit in Miami – the future hub of longevity sciences in the United States. The event will spotlight the latest advancements in healthy human longevity research and unite the local community for an evening of networking, collaboration, and celebration. With a fundraising goal of $250,000, the summit aims to support cutting-edge research projects on biological aging and chronic disease.

The event will welcome a mix of participants, including longevity enthusiasts, venture capitalists, private equity professionals, philanthropists, PhDs, MDs, students, community members, local government representatives, business owners, and ultra-high-net-worth (UHNW) individuals. Attendees can look forward to a presentation by LongeVC, panel discussions, and an exclusive interview with leading experts in the longevity sector and beyond.

With attendance limited to just 120 people, the LSF is fostering an intimate environment for high-profile engagement and innovative action. The summit presents a great opportunity to delve into this rapidly expanding field and contribute to the development of innovative, life-saving therapies.

“In addition to raising funds for high-quality fundamental research, our ambition is to position Miami as a hub for accessible longevity sciences, treatments, and care, building strong collaborations that yield tangible results for the advancement of groundbreaking research,” says Joshua C. Herring, President & CEO of the Longevity Science Foundation. “This summit serves as a catalyst, setting the stage for future growth and innovation in the field.”

The Longevity Science Summit will take place in Downtown Miami. The final venue details and agenda are currently being finalized and will be communicated to those who express interest in attending. The summit will span 6 to 7 hours, featuring opening remarks by Joshua C. Herring (the Longevity Science Foundation) and Michaeljohn Green (Miami Downtown Development Authority). Additional programming may be announced, with updates on the schedule and location shared as plans solidify.

Confirmed Speakers:

Kayla Barnes-Lentz (LYW Wellness)
Dr. Jose Antonio (International Society of Sports Nutrition)
Ella Davar, RD (Longevity Dietician, Founder of Gut-Brain Method)
Dr. James Galvin (University of Miami, Miller School of Medicine)
Dr. Ravindra Ganesh (Baptist Health Concierge Medicine)
Sergey Jakimov (LongeVC)
Dr. Richard Siow (Ageing Research at King’s College London)
Prof. Pawel Swietach (University of Oxford, Department of Physiology, Anatomy & Genetics)
Dr. Walter Neto (Serucell)

Supporting Companies and Sponsors Include:

Miami Downtown Development Authority
LongeVC
Baptist Health Concierge Medicine
Muhdo Health
Bean Intellisphere Group
Ageing Research at King’s College London (ARK)

Ambassadors and Partners:

European Society of Preventive Medicine (ESPM)
Longevity Journal
Dr. Deborah A. Finley
Demetri Kachevas

Proceeds from the event will continue to drive forward vital scientific research, exemplified by the LSF’s grant to the University of Oxford to investigate metabolic mechanisms of aging in the heart, as well as initiatives focused on female fertility, women’s health, and longevity. Attendees are encouraged to make donations either before or during the summit.

Join us in shaping the future of longevity research.

Press & Attendance

Lev Dvornik

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The Blog

Building a Future Free of Age-Related Disease

Senescence against cancer

Preventing the SASP at its root

Protecting cells from DNA damage

Effects in female mice

Literature

An essential protein

Aging too quickly

Restoring youth

Better looks and healthier minds

Promising, but there are still many unknowns

Literature

What can go wrong in five days?

Altered insulin responses

Is it “brain first”?

Literature

A drug on its way to the clinic

What elamipretide affects

What elamipretide doesn’t affect

Literature

About LongX

Contact

Shedding light on senescence

The answer is on the surface

Telling good from evil

Targeting LAMP1

Literature

Resilience versus decline

Teaching old mice new tricks

Senolytics appear to help

Literature

Buck Institute

National Innovation Centre for Ageing

International Institute for Longevity

Exposome Moonshot Forum

Literature

Slowdown in life expectancy increase

Country-level analysis

Cardiovascular diseases, cancers, and COVID-19

Avoiding risk

Funding healthcare

Diet and physical activity are the foundation of health and longevity

Literature

A paradox of size

The correlation between body size and cancer

The paradox is dead, long live the paradox

Literature

A system tightly tied together

A metabolic target

Increases in histones and ROS

Benefits for mice

Literature

Klotho has various forms

Improvements in lifespan

Improvements to tissues and performance

Literature

From East Asia to the clinic

Extending lifespan

Strengthening muscle

Improved aging markers

Molecular pathways

Senotherapeutic potential

Literature

A deeper dive

The exposome and mortality

Connection to aging and diseases

Genes are less important (exceptions apply)

Literature

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