Longevity Papers

This study investigated the role of mitochondrial function in aortic aging. As the aorta ages, it becomes stiffer and less compliant, increasing the risk of aneurysmal disease, hypertension, and diastolic dysfunction. Given the role of mitochondrial dysfunction in non-age related aortopathies and as a hallmark of aging, we investigated its contribution to the aging aorta. Both male and female young (5-6 month) and aged (24-25 month) C57Bl/6J mice received mitochondrial-targeted peptide elamipretide (ELAM; SS-31) for 8 weeks. ELAM restored complex II-linked respiration in aged mice to values seen in young mice, while also improving relative phosphorylative flux. ELAM treatment also reduced inflammatory MMP9 expression and elastin breaks in aged mice. Bulk RNAseq analysis revealed that ELAM treatment significantly affected the aortic transcriptome in an age-dependent manner, reducing the expression of senescent and associated pro-inflammatory genes. Mitochondrial dysfunction thus drives aortic aging and is a potential therapeutic target for future study.

Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated {beta}-galactosidase (SA-{beta}Gal) activity is a well established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naive CD4 and CD8 T cells displaying high SA-{beta}Gal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-{beta}Gal-high naive T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naive CD4 SA-{beta}Gal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naive T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan of

Ageing is the most important risk factor for many common human diseases, including cancer, diabetes, neurodegeneration and cardiovascular disease. Consequently, combating ageing itself has emerged as a rational strategy for addressing age-related multimorbidity. Over the past three decades, multiple genetic and pharmacologic interventions have led to substantial extension of lifespan and healthspan in model organisms. However, it is unclear whether these interventions target the causal mechanisms of ageing or downstream consequences. Ample evidence suggests that DNA damage to the somatic genome is a major causal mechanism of ageing, which compromises essential cellular functions such as transcription and replication, and leads to cellular senescence, apoptosis and mutations. Recently, new concepts have emerged to target the main consequences of DNA damage and enhance DNA repair capacities, thereby extending maintenance of the genome. Here, we review advances in this field and discuss approaches to pharmacologically mitigate the adverse effects of DNA damage to delay ageing, prevent mutation-driven cancer and mitigate age-related degenerative diseases.

Retinal age has emerged as a promising biomarker of aging, offering a non-invasive and accessible assessment tool. We developed a deep learning model to estimate retinal age with enhanced accuracy, leveraging retinal images from diverse populations. Our approach integrates self-supervised learning to capture chronological information from both snapshot and sequential images, alongside a progressive label distribution learning module to model biological aging variability. Trained and validated on healthy cohorts (34,433 participants from the UK Biobank and three Chinese cohorts), the model achieved a mean absolute error of 2.79 years, surpassing previous methods. When applied to broader populations, analysis of the retinal age gap-the difference between retina-predicted and chronological age-revealed associations with increased risks of all-cause mortality and multiple age-related diseases. These findings highlight the potential of retinal age as a reliable biomarker for predicting survival and aging outcomes, supporting targeted risk management and precision health interventions.

Dogs serve as ideal research subjects for aging studies. In this study, 9 aging-related cell populations are identified through single-cell RNA sequencing of dogs of different ages. Additionally, 9 CD8+ T cell senescence-specific markers conserved across species are identified. Furthermore, multi-omics technology is employed to characterize 17 transcriptional and protein markers, along with 5 metabolic markers, associated with stem cell aging. Penitrem A and UDP-N-acetylglucosamine are further validated as two consistent metabolic markers of both individual and cellular senescence. A customized metabolic assessment system and blood-based assessment framework specifically for aging dogs are developed. Notably, it is demonstrated that mesenchymal stem cells, particularly those overexpressing NMNAT1, can delay or reverse aging in dogs. This study sheds light on the mysteries of aging from multiple perspectives and provides a broad target for future research efforts aimed at uncovering the complexity of this fundamental biological process.

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/- tert-/- double-mutant animals and observed a thorough rescue of tert-/- phenotypes. At the cellular level, lack of cGAS-STING in tert mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telomerase mutant animals.

Aging is a major risk factor for insulin resistance and type 2 diabetes, driven in part by declining pancreatic beta cell function. While calorie restriction (CR) initiated early in life improves metabolic health and preserves beta cell function, its impact when initiated later in life remains unclear. We implemented a two-month, 20% CR intervention in 72-week-old male mice and assessed in vivo glucose homeostasis and beta cell function using meal tolerance tests, single cell RNA-sequencing, and confocal microscopy. We found that old mice exposed to CR have significantly improved glucose tolerance due to higher insulin sensitivity, which drives a two-fold reduction in glucose-stimulated beta cell insulin secretion. At the molecular level, CR enhanced beta cell proteostasis by downregulating ER stress pathways. Remarkably, CR reprogrammed the alpha cell transcriptome to suppress antigen presentation pathways and cytokine signaling pathways, including major histocompatibility complex class I (MHC-I) signaling. These transcriptional changes correlated with profound reduction in the density of adaptive immune cells in aging islets, including a near-complete loss of cytotoxic CD8+ T cells due to weakened intercellular communication between antigen-presenting cells with T and B lymphocytes. Importantly, aging human alpha cells from non-diabetic donors display similar proinflammatory phenotypes, including higher expression of MHC-I antigens that correlates with higher density of Cd8+ cells in aging human pancreases. Together, these findings demonstrate that CR remodels aging alpha and beta cell structure-function to modulate immune cell interactions in aging pancreases to mitigate age-related immune activation and islet inflammation.