Longevity Papers

The steroid hormone 5-androstene-3{beta},17{beta}-diol (ADIOL) was discovered in humans nearly a century ago, yet its physiological roles remain poorly defined. Here, we show that fasting and caloric restriction, two forms of dietary restriction, induce transcriptional upregulation of genes encoding CYP11A1, CYP17A1, and 17{beta}-hydroxysteroid dehydrogenase family enzymes, promoting ADIOL biosynthesis. ADIOL, in turn, acts on the nervous system to reduce levels of kynurenic acid, a neuroactive metabolite linked to cognitive decline and neurodegeneration. This effect requires NHR-91, the C. elegans homolog of estrogen receptor {beta}, specifically in the RIM neuron, a key site of kynurenic acid production. Consistent with the known benefits of fasting and caloric restriction on healthspan, enhancing ADIOL signaling improves multiple healthspan indicators during aging. Conversely, animals deficient in ADIOL signaling exhibit reduced healthspan under normal conditions and in genetic models of caloric restriction, underscoring the functional significance of this pathway. Furthermore, ADIOL suppresses cellular stresses induced by the Alzheimer\'s-associated APOE4 variant, highlighting its potential as a neuroprotective agent. Notably, ADIOL does not significantly impact lifespan, indicating that its healthspan benefits are not simply a byproduct of lifespan extension. Together, these findings establish a physiological role for ADIOL in mediating the neuroprotective and pro-healthspan effects of fasting and caloric restriction and suggest that boosting ADIOL signaling may help narrow the gap between lifespan and healthspan. This positions ADIOL as a promising mimetic of dietary restriction effects on healthspan that could be used as a therapeutic strategy for age-related neurodegenerative conditions.

RNA engineering has yielded a new class of medicines but faces limitations depending on RNA size and function. Here we demonstrate the synthesis and enzymatic stabilization of telomerase RNA component (TERC), a therapeutically relevant long non-coding RNA (lncRNA) that extends telomere length and replicative lifespan in human stem cells. Compared with therapeutic mRNAs, engineered TERC RNA (eTERC) depends on avoiding nucleoside base modifications and incorporates a distinct trimethylguanosine 5' cap during in vitro transcription. We show that the non-canonical polymerase TENT4B can be repurposed to enzymatically stabilize synthetic RNAs of any size by catalysing self-limited 2'-O-methyladenosine tailing, which is critical for optimal eTERC function in cells. A single transient exposure to eTERC forestalls telomere-induced senescence in telomerase-deficient human cell lines and lengthens telomeres in induced pluripotent stem cells from nine patients carrying different mutations in telomere-maintenance genes, as well as primary CD34

Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei et al. (Cell 188:1-22, 2025) address this limitation by engineering human embryonic stem cell-derived MPCs with enhanced FOXO3 activity (termed SRCs). Intravenous administration of FOXO3-SRCs to aged cynomolgus macaques significantly slowed aging across multiple organs compared to wild-type MPCs. SRC treatment improved cognitive performance, preserved brain structure, protected bone integrity, and rejuvenated immune function. Transcriptomic and DNA methylation aging clocks revealed substantial reductions in biological age, with the most pronounced rejuvenation observed in the reproductive system, skin, lung, muscle, and hippocampus. These effects were partly attributed to SRC-derived exosomes enriched in gero-protective proteins and metabolites. Importantly, SRCs exhibited robust safety, showing no tumorigenicity or immunogenicity. This work positions FOXO3-enhanced MPCs and their exosomes as promising candidates for systemic anti-aging interventions, shifting the therapeutic paradigm from treating individual diseases to targeting the aging process itself.

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 (vgll3), a transcription cofactor previously linked to age at maturity in humans and male Atlantic salmon through GWAS, as an antagonistically pleiotropic gene in the turquoise killifish (Nothobranchius furzeri). Selective disruption of vgll3 isoforms accelerates male growth and maturation in an isoform- and dose-dependent manner. Transcriptomic analysis, supported by cellular and physiological phenotypes, indicated increased cell proliferation and elevated germline production. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit elevated age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.

α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.