LongeCityNews Last Updated: 11 February 2026 - 10:42 PM

Rapamycin and other mTOR inhibitors mimic some of the mechanisms making up the response to calorie restriction. Their most interesting effect is to increase the operation of autophagy in cells. Autophagy is a collection of processes responsible for recycling damaged or unwanted proteins and structures in the cell. A large proportion of the approaches shown to modestly slow aging in yeast, worms, flies, and mice are characterized by increased or more efficient autophagy; it is a universal response to stress of any sort placed upon a cell. Too much autophagy can be a bad thing, but a modest increase improves health in the context of the dysfunctional, damaged environment of aged tissues.

Another feature of mTOR inhibitors, and the age-slowing interventions that are characterized by upregulated autophagy, is that the burden of harmful, inflammatory senescent cells that linger in aged tissues is reduced. The present thinking on this topic is that this reduction does not occur because senescent cells are destroyed by the intervention, but rather that the pace at which cells become senescent is reduced. This seems sensible: more autophagy allows cells to better maintain function and resist damage, and thus fewer cells will be tipped over the line into senescence in response to damage.

Here, however, researchers argue that, at least in immune cells, the effects of mTOR inhibition on cellular senescence do not emerge from autophagy. Instead, there is a direct effect on the burden of DNA damage in these cells, and it is that reduced DNA damage that leads to a reduced number of cells becoming senescent. Further work will have to be conducted in order to fully understand how exactly mTOR inhibition produces this outcome.

Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability.

In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition.

To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

Transferring microbiota from young to aged mice helped to restore molecular signaling necessary for proper intestinal function and improved the regenerative capacity of intestinal stem cells [1].

Everyday companions

Bacteria, viruses, and other microbes are well-known as agents that cause disease and should be avoided. However, the microbes that make us sick, while more noticeable, are in the minority. The majority of microbes are either harmless or beneficial, and we all coexist with millions of them every day. Moreover, we cannot function properly without their assistance. Researchers refer to these microbes as microbiota: microbes that reside both inside and outside the human body and are especially abundant in the intestine.

Microbiota affect multiple aspects of health, including digestion and immune modulation, along with aging processes; aging-related changes in microbiotal composition are associated with age-related conditions such as obesity [2], inflammatory bowel disease [3], and irritable bowel syndrome [4].

The microbiome matters

The authors of this study focused on the aging processes in the intestinal epithelium. Aging is associated with reduced intestinal epithelial turnover and a decline in the self-renewal and differentiation abilities of its stem cells. At the molecular level, previous studies have linked this functional decline in intestinal stem cells to reduced canonical Wnt signaling [5].

The researchers began by assessing Wnt gene expression in the intestinal crypts of mice, which are home to these stem cells. Microbiotal abundance was found to affect Wnt signaling, and its removal reduces regenerative capacity after irradiation.

Transferring microbiota

One approach that has the potential to restore age-related changes in microbiotal composition is fecal microbiota transfer. Those researchers performed heterochronic fecal microbial transfers (FMTs), transferring young microbiota to aged animals and aged microbiota to young animals, along with control groups of homochronic control transfers (young microbiota to young animals and aged microbiota to aged animals).

Seven days after this transfer, an analysis suggested that it impacted the composition of the microbiome of the recipient, “with the age clock of the microbiota in the intestine of the recipient animal set to the clock of the FMT donor.”

An analysis of Wnt gene expression found that the control group of young animals that received young microbiota had more expression of Wnt3 and of the canonical Wnt signaling genes Ascl2 and Lgr5, as well as the intestinal stem cell marker gene Olmf4 in crypts, compared to aged animals that received aged microbiota.

When aged animals received young fecal samples, the expression levels of central canonical Wnt signaling genes in aged crypts and intestinal stem cells increased compared to aged animals that received an aged microbiome. Transferring young microbiota to aged animals also improved the function of aged intestinal stem cells, specifically the regeneration of intestinal epithelial tissue.

“This reduced signaling causes a decline in the regenerative potential of aged intestinal stem cells,” said co-author Yi Zheng, PhD, director of the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s. “However, when older microbiota were replaced with younger microbiota, the stem cells resumed producing new intestine tissue as if the cells were younger. This further demonstrates how human health can be affected by the other life forms living inside us.”

Complex interactions

The microbiome contains many species of microbes, and the researchers investigated which of them affect Wnt signaling and intestinal stem cells. To narrow their search, they identified 7 microbial groups whose abundance was affected by both aging and the transfer of young microbiota to aged animals. One of those microbial species was Akkermansia muciniphila, whose abundance was higher in the aged animals that received aged microbiota and young animals that received aged microbiota compared to the young animals that received young microbiota and the aged animals that received young microbiota.

Akkermansia muciniphila’s role in the biology of aging appears complex and ambiguous. On one hand, elevated levels of this bacterium are generally considered beneficial for the intestine [6], and it has been shown to extend the lifespan of progeroid animals, which suffer from accelerated aging [7]. Several studies have also shown enrichment of Akkermansia muciniphila in the guts of healthy, long-lived older adults [8]. However, on the other hand, different reports show that centenarians, who are considered to be ‘successful agers’, have reduced levels of Akkermansia muciniphila [9], suggesting that its impact on aging processes might be negative.

In this study, orally providing more Akkermansia muciniphila to young and aged mice increased its levels in the the first and shortest segment of the small intestine (the duodenum) of aged mice, while levels in young mice were unchanged. The researchers suggest that this is due to insufficient mucin levels in the young intestinal epithelium. Mucin serves as a food source for Akkermansia muciniphila, and mucin levels in young animals may be insufficient to support its abundance; however, this was not tested.

Akkermansia muciniphila negatively impacted the expression levels of canonical Wnt signaling genes in aged animals. In aged mice, following the administration of this bacterium, the researchers observed a further reduction in Ascl2 and Lgr5 gene levels compared to untreated age-matched controls, but only a small change in young mice that received Akkermansia muciniphila. Further experiments also indicated a “reduced regenerative potential of aged intestinal stem cells exposed to A. muciniphila.”

The increased levels of Akkermansia muciniphila in the intestines of aged mice following treatment were accompanied by changes in the levels of other microbes. Researchers hypothesized that it is possible that these other microbes may be partially responsible for the observed changes in intestinal function and gene expression following its administration. However, the changes of other microbiome components and their impact on Wnt signaling and the regenerative capacity of intestinal stem cells were not evaluated in this study.

Despite the lack of mechanistic understanding, this study contributed to the growing body of scientific evidence demonstrating the microbiome’s impact on intestinal aging. As concluded by the corresponding author, Hartmut Geiger, PhD, director of the Institute of Molecular Medicine at Ulm University and former member of the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s, “Our findings show that younger microbiota can prompt older intestine to heal faster and function more like younger intestine.”

Literature

[1] Nalapareddy, K., Haslam, D. B., Kissmann, A. K., Alenghat, T., Stahl, S., Rosenau, F., Zheng, Y., & Geiger, H. (2026). Microbiota from young mice restore the function of aged ISCs. Stem cell reports, 102788. Advance online publication.

[2] Sun, L., Ma, L., Ma, Y., Zhang, F., Zhao, C., & Nie, Y. (2018). Insights into the role of gut microbiota in obesity: pathogenesis, mechanisms, and therapeutic perspectives. Protein & cell, 9(5), 397–403.

[3] Zuo, T., & Ng, S. C. (2018). The Gut Microbiota in the Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Frontiers in microbiology, 9, 2247.

[4] Theodorou, V., Ait Belgnaoui, A., Agostini, S., & Eutamene, H. (2014). Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome. Gut microbes, 5(3), 430–436.

[5] Nalapareddy, K., Nattamai, K. J., Kumar, R. S., Karns, R., Wikenheiser-Brokamp, K. A., Sampson, L. L., Mahe, M. M., Sundaram, N., Yacyshyn, M. B., Yacyshyn, B., Helmrath, M. A., Zheng, Y., & Geiger, H. (2017). Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells. Cell reports, 18(11), 2608–2621.

[6] Naito, Y., Uchiyama, K., & Takagi, T. (2018). A next-generation beneficial microbe: Akkermansia muciniphila. Journal of clinical biochemistry and nutrition, 63(1), 33–35.

[7] Bárcena, C., Valdés-Mas, R., Mayoral, P., Garabaya, C., Durand, S., Rodríguez, F., Fernández-García, M. T., Salazar, N., Nogacka, A. M., Garatachea, N., Bossut, N., Aprahamian, F., Lucia, A., Kroemer, G., Freije, J. M. P., Quirós, P. M., & López-Otín, C. (2019). Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nature medicine, 25(8), 1234–1242.

[8] Zeng, S. Y., Liu, Y. F., Liu, J. H., Zeng, Z. L., Xie, H., & Liu, J. H. (2023). Potential Effects of Akkermansia Muciniphila in Aging and Aging-Related Diseases: Current Evidence and Perspectives. Aging and disease, 14(6), 2015–2027.

[9] Wang, F., Yu, T., Huang, G., Cai, D., Liang, X., Su, H., Zhu, Z., Li, D., Yang, Y., Shen, P., Mao, R., Yu, L., Zhao, M., & Li, Q. (2015). Gut Microbiota Community and Its Assembly Associated with Age and Diet in Chinese Centenarians. Journal of microbiology and biotechnology, 25(8), 1195–1204.

Structures of the endoplasmic reticulum are where the folding of newly synthesized proteins takes place in the cell. The endoplasmic reticulum is also involved in a range of other activities relevant to the manufacture of proteins and other molecules, such as quality control and recycling of misfolded proteins. Researchers here describe how the endoplasmic reticulum changes in structure with age, and link this to changes in the recycling of endoplasmic reticulum structures via autophagy. They suggest that these changes are compensatory, but become maladaptive in later life.

The morphological dynamics of the endoplasmic reticulum (ER) have received little attention in the context of ageing. Here we established tools in C. elegans for high-resolution live imaging of ER networks in ageing metazoans, which revealed profound shifts in ER network morphology that are driven by autophagy of ER components (ER-phagy). Across a variety of tissues, we consistently found a decrease in ER protein levels and cellular ER volume, and a structural shift from densely packed sheets to diffuse tubular networks. The ER content also declined in yeast and mammalian systems, and proteomic atlases of the ageing process in worms and mammals showed that age-onset collapse in ER proteostasis function is a broadly conserved aspect of the ageing process

We found that Atg8-dependent ER-phagy is the key mechanism driving turnover and remodelling of the ER network during ageing. A targeted screen for mediators in C. elegans revealed that the physiological triggers of ER-phagy in an ageing metazoan model are cell-type specific. Tissue-specific roles of ER-phagy receptors may help to explain why the ubiquitous macroautophagy machinery seems to be a universal requirement for longevity assurance in metazoan genetic studies, whereas the importance of selective ER-phagy mediators has been slower to emerge. Subsequently, we demonstrate that the two pathways capable of blocking age-associated ER-phagy, TMEM-131 and IRE-1-XBP-1, are required for mTOR-dependent lifespan extension in C. elegans.

Importantly, not all changes that occur during ageing reflect pathogenesis. The earliest remodelling events are likely to be adaptive responses to the cessation of developmental programmes and rising metabolic and cellular damage. We propose a model where age-dependent ER remodelling serves as an adaptive step in the ageing process associated with reprogramming of the proteostasis network. However, although data indicate that the net effect of ER-phagy on lifespan is positive, we speculate that early pronounced remodelling of ER structures is likely to trigger pleiotropic trade-offs later, especially in longer-lived cells and animals.

Link: https://doi.org/10.1038/s41556-025-01860-1

In recent years, researchers have established that a great many proteins can aggregate to some degree in cells of the aging brain, and that this likely contributes to loss of function. This issue is distinct from the few well-known proteins such as amyloid-β that aggregate to a very large degree in the context of neurodegenerative conditions. Here, researchers provide evidence for this generalized aggregation across more than a thousand proteins to contribute to impaired maintenance of synapses in the aging brain.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing. Here we engineered tools that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age.

The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1038/s41586-025-09987-9