Longevity Papers

Theobromine, a commonly consumed dietary alkaloid derived from cocoa, has been linked to extended lifespan in model organisms and to health benefits in humans. We examined associations between circulating theobromine intake, measured using serum metabolomics, and blood-based epigenetic markers of biological ageing in two European human population-based cohorts. Serum theobromine levels were significantly associated with reduced epigenetic age acceleration, as measured by GrimAge (p<2e-7) and DNAmTL (p<0.001) in over 500 individuals from the TwinsUK cohort, and both signals replicated in 1,160 individuals from the KORA cohort (p = 7.2e-08 and p = 0.007, respectively). Sensitivity analyses including covariates of other cocoa and coffee metabolites suggest that the effect is specific to theobromine. Our findings indicate that the reported beneficial links between theobromine intake on health and ageing extend to the molecular epigenetic level in humans.

Efficient clearance of central nervous system (CNS) waste proteins and appropriate immune surveillance is essential for brain health. These processes are facilitated by lymphatic networks present in the meninges that drain cerebrospinal fluid (CSF). Age-related impairments to meningeal lymphatic drainage contribute to CNS waste accumulation and immune dysfunction, yet the underlying mechanisms remain poorly understood. Here, we identify extracellular matrix (ECM) remodeling in the aged dura as a key driver of CSF clearance deficits, demonstrating that peri-lymphatic collagen accumulation disrupts lymphatic function. Exploring immune-derived factors contributing to this ECM remodeling, we identify transforming growth factor beta 1 (TGFβ1) as a major regulator using primary human dural fibroblasts. Using a novel mouse model with constitutively active TGFβ receptor 1 (TGFβR1) signaling in dural fibroblasts, we show that excessive peri-lymphatic collagen deposition impairs meningeal lymphatic drainage and alters meningeal immunity. Mechanistically, we reveal that ECM-associated matrix stiffness disrupts lymphatic junction integrity and impairs lymphangiogenesis in human lymphatic endothelial cells. These findings establish dural immune cell and fibroblast-mediated ECM remodeling as a critical regulator of CSF clearance and highlight it as a potential therapeutic target for restoring brain waste clearance in aging.

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

Physical activity (PA) is one of the most fundamental of all traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program (MVP), we conducted genetic analyses of leisure, work, and home-time PA. For leisure, for individuals of European (EUR) ancestry, n=189,812 and SNP-based heritability (h2)=0.083+/-0.005; for African ancestry, n=27,044; h2= 0.034+/-0.017; and for Latin-American ancestry, n=10,263; h2= 0.083+/-0.036. EUR and cross-ancestry meta-analyses with UK Biobank identified 67 and 70 lead variants. Leisure-time PA was genetically distinct from PA at home or work, with the latter two showing less health benefit on pathologies and lifespan. Mendelian randomization analyses showed protective effects of leisure-time PA on cardiovascular and respiratory system diseases, metabolic traits, aging, and other traits, and there was protective role of leisure-time PA against COVID-19 hospitalization ({beta}=-0.067+/-0.016; p-value=2.8x10-5). These findings provide new insights into the biology of PA, showing the causal health benefits of leisure-time PA.