Longevity Papers

The pregnane X receptor (Pxr) regulates metabolism and inflammation, but its roles in bone homeostasis remain elusive. This study demonstrates that Pxr deficiency in bones induces osteoporotic phenotypes, with reduced trabecular bone mass, impaired osteogenesis, increased inflammation, and apoptosis. RNA sequencing reveals downregulation of the PI3K/Akt signaling pathway in Pxr-deficient bones, a key pathway linked to cell survival and differentiation. In vitro, primary bone marrow mesenchymal stem cells (BMSCs) with Pxr deficiency exhibited inhibited antioxidant enzyme activity, elevated intracellular reactive oxygen species level, activated pro-inflammatory cytokines, suppressed PI3K/Akt pathway, enhanced apoptosis, and decreased osteogenic differentiation. Conversely, Pxr overexpression in BMSCs from aged mice restores PI3K/Akt activation, mitigates apoptosis, and rescues osteogenic differentiation, with these multidirectional beneficial effects abrogated by a PI3K/Akt inhibitor. Moreover, both genetical overexpression of Pxr and pharmacological activation of Pxr improve bone quality in aged mice. These findings identify Pxr as a key regulator of bone homeostasis via the PI3K/Akt pathway, suggesting Pxr as a potential treatment target for age-related bone loss.

Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial ROS accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Histone H4K16 acetylation (H4K16ac) is a key epigenetic mark essential for chromatin structure and DNA repair, which is substantially reduced in the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS). The specific enzymes governing H4K16ac homeostasis, particularly the deacetylase responsible for its loss in HGPS, remain poorly defined. Here, we sought to identify the enzymes regulating H4K16ac and determine if their inhibition could rescue HGPS-associated cellular defects. Using systematic siRNA screening in HeLa and U2OS cells, we confirmed that KAT8/MOF is the principal H4K16 acetyltransferase. Surprisingly, we identified HDAC2 as the dominant class I histone deacetylase for H4K16ac; knockdown of the highly homologous HDAC1 had no effect. While SIRT1 knockdown also increased H4K16ac, its contribution was minimal in HGPS vascular smooth muscle cells (VSMCs) compared to HDAC2. Crucially, selective pharmacological inhibition of HDAC2, but not SIRT1, robustly restored H4K16ac levels in HGPS VSMCs. This restoration led to a significant rescue of premature aging phenotypes, including improvements in nuclear morphology, preservation of proliferative capacity (Ki67) at late passages, and a significant reduction in cellular senescence. The effects of HDAC2 inhibition on cellular senescence and nuclear morphology suggests that HDAC2-mediated histone deacetylation contributes directly to the pathological features of HGPS, extending the functional impact of HDAC2 inhibition beyond DNA repair defects to fundamental aspects of cellular aging.

Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is only now being fully investigated. In the Caenorhabditis elegans nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the insulin-like DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan. Here we show that ubiquitous degradation of DAF-2 in male C. elegans increases median lifespan by more than 440%, one of the longest lifespan extensions by a single intervention to date. Conversely, degrading DAF-2 in the male germline decreased lifespan, opposite of its effect in hermaphrodites. Using male mating and reproductive success as a meaningful ecological and neurophysiological measure of healthspan, we found that ubiquitous degradation of DAF-2 greatly prolongs reproductive health, likely by prolonging function of the male intromittent organ in the tail. This work highlights the importance of studying sex differences in aging and highlights the utility of using C. elegans males to understand the underlying basis of enhanced lifespan and healthspan.

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SON-AVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SON-AVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SON-AVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

Long duration spaceflight is associated with neurological symptoms in astronauts, yet the underlying molecular mechanisms remain unclear. Using human brain organoids cultured aboard the International Space Station, we analyzed three independent spaceflights to demonstrate that exposure to the space environment triggers Space Induced Neural Senescence (SINS), characterized by chromatin remodeling, mitochondrial dysfunction, and activation of viral-like transcriptional programs in the absence of infection. Multiomics analyses identified upregulation of endogenous LINE-1 (L1) retroelements, whose activity was markedly enhanced in organoids lacking MECP2, a known L1 repressor implicated in Rett syndrome. The resulting accumulation of cytoplasmic L1 DNA elicited an IL6 mediated inflammatory and neurotoxic response, which was reversed by reverse transcriptase inhibitors (RTi) such as lamivudine or stavudine. Parallel preclinical experiments in Mecp2-deficient mice confirmed that RTi treatment restored neuronal morphology, synaptogenesis, function, cognition, and survival. These findings reveal that the space environment reactivates dormant genomic retroelements, providing an unexpected mechanistic insight into astronaut neurobiology and identifying a potential therapeutic strategy for both space-induced and terrestrial neurological conditions. Our pioneering study demonstrates the value of space-enabling research in accelerating drug discovery and the treatment of diseases on Earth.

Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.