Fight Aging!

Naked mole-rats are an unusually long-lived mammalian species, of a similar size to mice but with a life span of decades rather than just a few years. This species also exhibits a near complete absence of cancer and very little age-related decline in function until very late in life. Investigations of their biochemistry have uncovered a range of interesting differences, such as senescent cells that are far more benign than their counterparts in other mammals, more efficient protein synthesis, more efficient DNA repair (such as an improved version of the cGAS protein), and more. That naked mole-rats live underground in oxygen poor environments, with a corresponding lack of predation, has prompted the evolution of greater longevity and the necessary co-evolution of the many features needed to support that longevity, such as improved cell resilience to common stresses.

In today's open access paper, researchers examine the gut microbiome in naked mole-rats. In mice and humans the composition of the gut microbiome changes with age, in ways that provoke greater inflammation and diminish the supply of beneficial metabolites. Animal studies have shown that restoring a youthful composition, such as via fecal microbiota transplantation from a young donor, improves health and extends life. Perhaps unsurprisingly, all things considered, the results in the paper here show that naked mole-rats exhibit very little change in the composition of the gut microbiome over a life span. Why this is the case is an interesting question, however. It perhaps argues for the hypothesis that changes in gut microbiome composition are downstream of the aging of the immune system, as it becomes ever less capable of suppressing populations of undesirable microbes.

The naked mole-rat microbiome is associated with healthy aging and social structure

The gut microbiome plays a pivotal role in health and disease, modulating digestion and xenobiotic processes, regulating metabolism, influencing epithelial development, and altering immune function. When the microbiome is dysregulated, as may occur during aging, it may contribute to myriad chronic diseases, such as cardiovascular disease, diabetes, and cognitive impairment. Similarly, therapeutic interventions that modify the microbiome with probiotics reportedly have been effective in the treatment of age-related cognitive impairment and sarcopenia and may even delay or abrogate the overall physiological declines that occur with advancing age.

Here, we investigate the naked mole-rat (NMR; Heterocephalus glaber) and its unique microbiome. These small (35-45 g) rodents are notable for both their unusual eusocial lifestyle and successful aging profile: breeding is monopolized by one female (the "queen") within a colony, with the result that although most NMRs remain in their natal colony, less than 1% of all individuals have the opportunity to reproduce over their exceptionally long lifespans (more than 40 years). In addition to their extraordinary longevity, NMRs show a lack of demographic aging, with no increased risk of dying in older animals, and well-maintained physiological, metabolomic, and biochemical function with advancing age. NMRs are also resistant to chronic age-associated diseases (e.g., cancer, neurodegeneration, and cardiovascular diseases). These atypical features suggest they are able to successfully retard, delay, or abrogate the functional declines that commonly accompany the aging process in other mammals.

Comparing fecal samples from NMR individuals over different social ranks and over a span of more than three decades. In contrast to a cohort of C57BL6/J mice, which showed extensive age-related changes, we found little difference in the microbiota of NMRs from different age cohorts. Only the archaea Methanomassiliicoccus intestinalis, which was present in the NMR gut but not the murine gut, showed an increased proportion with older age. Pregnant queens were found to have higher microbial diversity, potentially a consequence of their aggressive coprophagia. Overall, these findings provide a rich and dynamic picture of the NMR microbiome and starting points for future investigation.

Presently largely irreversible lung disease like idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were one of the first conditions targeted for the development of senolytic therapies to clear senescent cells. A range of evidence supports a prominent role for an increased burden of senescent cells in airway and lung tissues in these conditions. Here, researchers discuss a more recent approach to senolytic therapy, employing a proteolysis-targeting chimera approach to make the cell break down one of the proteins involved in senescent cell survival. Senescent cells, unlike normal cells, are primed to undergo the programmed cell death of apoptosis. They are only held back from that fate by the activity of a few proteins, including BCLXL, which is the target here. When levels of BCLXL are dramatically reduced, senescent cells undergo apoptosis while normal cells are largely unaffected.

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD.

Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a, and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment.

These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.

Link: https://doi.org/10.1111/acel.70487

Senescent cells accumulate with age, but not all senescent populations are equal. Evidence suggests that some types of senescent cell cause more harm than others, and the research here is an example of this. Researchers find that a population of senescent macrophages in liver tissue acts as an important driver of chronic inflammation and dysfunction in liver aging and the metabolic liver disease associated with excess fat tissue that leads to cirrhosis and cancer. Senolytic therapies that selectively destroy the senescent macrophages reduce liver inflammation and liver dysfunction in mice, proving the point.

Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21+Trem2+ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling.

We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.

Link: https://doi.org/10.1038/s43587-026-01101-6