Longevity Papers

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

Aging drives physiological decline and predisposes individuals to multiple age-related pathologies, constituting a major global health challenge. Growth hormone receptor (GHR), a critical regulator of growth, development, and metabolism, has emerged as a potential therapeutic target. However, its precise role in aging and age-related diseases remains incompletely defined. Here, we demonstrate that hepatocyte-specific GHR knockout mice display accelerated aging-related phenotypes, characterized by shortened lifespan, enhanced cellular senescence, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging. Elevated circulating GH following hepatocyte-specific GHR ablation mediates adipose-liver crosstalk that promotes adipose lipolysis and CD36-dependent hepatic steatosis. Hepatocyte-specific GHR deficiency also promotes liver aging and aggravates age-related hepatic pathologies in both naturally aged and high-fat diet (HFD)-fed mice. Mechanistically, loss of hepatic GHR impairs STAT5b phosphorylation while upregulating PPARγ expression. Enhanced nuclear translocation of PPARγ activates transcription of Pdk4 and Cd36, leading to mitochondrial damage and ectopic lipid accumulation. Together, dysregulated lipid metabolism and mitochondrial dysfunction establish a self-amplifying vicious cycle that accelerates aging and its pathophysiology. Pharmacological inhibition of PDK4 in vivo effectively ameliorates the age-related pathologies induced by hepatocyte-specific GHR ablation. These findings identify hepatic GHR signaling as an important contributor to age-related hepatic pathology and a candidate node within the broader network of factors driving systemic aging phenotypes, highlighting hepatocyte GHR signaling as a promising therapeutic target for age-related liver disorders.

Epigenetic aging is a hallmark of chronic diseases. While such epigenetic changes can arise following tissue injury, the cell types most affected remain largely unknown. Here we built a cross-species single-cell multiomics atlas of DNA methylation, chromatin accessibility and transcription profiles from healthy, injured (human) and aged (mouse) kidneys. We found that tubular epithelial cells in diseased kidneys exhibit pronounced accelerated epigenetic aging and showed that this pathological state mirrors transcriptional trajectories observed during aging, driven by preferential dysregulation of lineage-specific genes lacking CpG islands. Spatially, these epigenetic changes mapped to pathological niches of unresolved repair. Co-profiling single-cell DNA methylation and 3D genome architecture revealed that epithelial repair states in disease undergo significant higher-order genome reorganizations, alongside activation of genes associated with renal decline. Together, our findings characterize a loss of epigenetic repression within coordinated three-dimensional chromatin structures and reduced local methylome integrity, which compromises epithelial cell identity during aging and impedes repair.

Frailty and cognitive decline are common among older adults, increasing risks of disability and loss of independence. We have previously demonstrated in mice that short session (≤10 minute) high-intensity interval training (HIIT) is an effective intervention for frailty, but benefits for cognitive function and reducing hallmarks of aging have not been examined. Thus, we studied 24-month-old female C57BL/6J mice from our previous study that remained sedentary or performed a 10-minute HIIT regimen 3-days-a-week for 8 weeks. We found HIIT improved cognitive aspects including an increase in T-maze alternation % and novel object recognition, but no differences were observed in Barnes maze or light-dark preference. To explore HIIT impacts on the hallmarks of aging, we examined liver, gastrocnemius muscle, and cortex brain tissues for mitochondria expression, autophagy, cellular senescence, and telomere length. HIIT increased expression of mitochondrial complexes I and V, as well as PGC1α and SIRT3 in all tissues. Autophagy marker beclin was elevated across all tissues, while p62 was increased in liver and muscle but not in the cortex, and LC3-II was lower in muscle and liver. Senescence marker p16 was lower in HIIT muscle and liver, whereas p21 decreased in liver but increased in muscle. Telomere lengths were greater in liver, but no changes in muscle or cortex. Additionally, within the group of sedentary mice, we identified differences in hallmarks of aging that potentially underlie frailty as measured using different mouse frailty assessment tools. These results highlight the potential for multi-tissue geroprotective benefits of short session HIIT to reduce frailty and improve cognition for healthy aging.

Erigeron breviscapus Hand-Mazz. (EBHM) is a well-documented herbal medicine with recognized antioxidant, anti-apoptotic, and anti-inflammatory bioactivities. However, its anti-senescence effects and the underlying mechanisms remain poorly understood. Here, we investigated the anti-senescence potential of EBHM employing Caenorhabditis elegans and SAMP8 mice. In C. elegans, EBHM treatment prolonged the average lifespan of C. elegans to a maximum of 18.68%, while also significantly enhancing stress resistance and motor function. The lifespan-extending effects of EBHM were abolished in mutants of aak-2, sir-2.1, daf-16, and cep-1. EBHM treatment increased p-AMPK/AMPK ratio and elevated levels of SIR-2.1 protein, facilitated the nuclear import of DAF-16::GFP as well as the upregulation of SOD-3::GFP expression, lowered MDA content, and enhanced the enzymatic activities of SOD, GSH-Px and CAT through a DAF-16-dependent mechanism. Furthermore, EBHM downregulated the mRNA levels of the pro-apoptotic genes cep-1and ced-3 (CASP3 homolog), while upregulating the anti-apoptotic gene ced-9 (Bcl-2 homolog) in C. elegans. In SAMP8 mice, EBHM reduced SA‑β‑gal‑positive cells, collagen deposition, and α-SMA expression in the liver and kidney, elevated the p-AMPK/AMPK ratio and SIRT1 expression, decreased levels of acetyl-FOXO3a, p53, acetyl-p53, p16, and p21, lowered MDA levels while enhancing antioxidant enzyme activities, diminished the proportion of apoptotic cells, downregulated Bax and CASP3, and upregulated Bcl-2. Collectively, these findings suggest that EBHM prolongs lifespan and healthspan in C. elegans and ameliorates aging‑associated tissue alterations in SAMP8 mice through activation of the AMPK-SIRT1 pathway, which enhances FOXO3a-dependent antioxidant defenses and modulates p53-mediated apoptosis, thereby alleviating oxidative stress and cellular damage.

Immunosenescence represents a central hallmark of organismal aging, characterized by a progressive decline in immune function, which compromises host defense and accelerates systemic aging. Hematopoietic stem cell (HSC) aging is a key contributor to this process, characterized by aberrant expansion, myeloid-biased differentiation, and impaired self-renewal, culminating in hematopoietic-immune imbalance. Although the expansion and survival advantages of aged HSCs have been well-demonstrated, the underlying mechanisms remain elusive. Here, we reveal that regulatory T cells (Tregs) within the bone marrow (BM) microenvironment actively safeguard the survival of aged HSCs via a previously uncharacterized signaling pathway. We identify a novel aged HSC subpopulation characterized by high expression of Baculoviral IAP Repeat Containing 6 (BIRC6), an apoptosis inhibitor. This BIRC6-high subpopulation is markedly expanded in aged mice and recapitulates the hallmarks of HSC aging. Mechanistically, cAMP derived from BM Tregs activates the PKA-CREB pathway in HSCs, activating Birc6 transcription, which reduces apoptotic priming in aged HSCs, thereby promoting hematopoietic-immune imbalance. Strikingly, targeted BIRC6 inhibition in HSCs using antibody-conjugated lipid nanoparticle-encapsulated antisense oligonucleotides (LNP-ASOs) significantly reverses hematopoietic-immune aging phenotypes and ameliorates age-associated immune dysfunction in middle-aged mice. LNP-ASO treatment dramatically rebalances immune cell production, reduces immunosenescence markers, and enhances vaccine responses in middle-aged mice. More importantly, this strategy was also effective in HSCs from middle-aged human donors, highlighting its potential for clinical translation. These findings elucidate a key microenvironmental pathway (Treg-cAMP-PKA-CREB-BIRC6) driving HSC aging and offer a novel strategy to ameliorate the aged hematopoietic system and combat age-related immune decline.

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing

Centuries ago, Thomas Sydenham famously wrote, "A man is as old as his arteries", highlighting the importance of the vasculature for health and healthy aging. Here, we review recent developments in vascular aging research, focusing on how microvascular aging drives tissue dysfunction and the emerging therapeutic opportunities for vascular rejuvenation. Although macrovascular aging has long been studied, microvascular aging remains an emerging frontier. Recent single-cell and multiomic technologies now allow unprecedented resolution of vessel wall cellular and molecular heterogeneity across organs throughout life. Beyond angiogenesis, hemodynamics, barrier function, coagulation and inflammation, the vessel wall is increasingly recognized as an instructive gatekeeper of organ function: endothelial and mural cells actively control surrounding parenchyma via angiocrine and pericrine signaling mechanisms, controlling organ function in health and disease. Integrating these technological and conceptual advances has reshaped our understanding of vascular aging, revealing organotypic vulnerabilities and intercellular mechanisms that drive systemic decline.

Aging is characterized by immunosenescence, encompassing, immune aging and inflammaging. Because immune competence is a critical determinant of lifespan and healthspan, targeting immunosenescence has become a major objective of geroscience. In this context, sirtuins have emerged as compelling therapeutic candidates.