Brain aging consists of a progressive loss of functional capacities, which is associated with a progressive cognitive decline and can lead to neurodegenerative diseases. Studies comparing the underlying molecular mechanisms of the human hippocampus between young and older adults remain scarce. In our study, we completed a transcriptomic analysis from hippocampal samples of different ages and performed 2 complementary analyses. A comparison between young and old groups revealed a set of genes differentially expressed in aged individuals linked to inflammation and immune system pathways, DNA repair, metabolism, or neural activity. Correlation analysis showed that the expression of an additional subset of 6 genes was associated with chronological aging. Among them, further analysis identified RAD23B as the most significant gene with a negative correlation of its mRNA and protein expression with age in the human hippocampus. Its expression was even lower in patients with Alzheimer's disease. RAD23B was mostly expressed in neurons and astrocytes, where studies in human primary cultures uncovered that it is required for cell survival and function. In summary, these results unravel dynamic gene expression changes that distinguish young from older adults and identify RAD23B as a putative biomarker and regulator of cell aging in the brain.

Age-related cellular changes negatively impact CD4+ T cell function. Our prior work showed that mitochondrial complex II (succinate dehydrogenase [SDH]) expression was upregulated in T cells from older (O) adults (60-80 years old). T cells from older adults also produced higher amounts of cytokines generally considered proinflammatory, such as Th17 cytokines IL-17A/F and IL-21, and the Th-17-supportive cytokine IL-6, compared to T cells from younger (Y) adults (25-40 years old). The objective of our study is to evaluate whether hyperactivation of SDH is required for the induction of proinflammatory cytokines and the mechanistic link between SDH and Th17 cytokine production. CD4+ T cells were isolated from lean normoglycemic younger (avg: 31.58 years; BMI 21.14 kg/m2) and older (avg: 64.81 years; BMI 21.95 kg/m2) adults. SDH was pharmacologically and genetically modulated, and mitochondrial structure, function, metabolites, and cytokine production were quantified. SDH activation in T cells from older adults induced heightened oxidation of succinate, disrupted the fumarate-to-succinate ratio, stabilized HIF-1α, and promoted Th17 cytokines. Genetic and pharmacological inhibition of SDH in T cells from older adults lowered proinflammatory cytokine production, whereas exogenous addition of cell-permeable succinate induced SDH protein in T cells from younger adults and recapitulated the proinflammatory Th17 profile observed in T cells from older adults. These data establish a mechanistic link between SDH and Th17 inflammation.

Early-life nutrition can exert long-lasting effects on later-life health. Given that lactose is extensively consumed during early mammalian development, this raises the intriguing possibility that lactose or its constituent galactose may exert beneficial nutritional programming effects. We tested here whether early-life (larval period) co-consumption of galactose and glucose (GALGLU; as in hydrolysed lactose) shapes later-life (adult) lifespan in Drosophila melanogaster. Larval GALGLU versus isocaloric glucose consumption (GLU) significantly extended the developmental time of larvae, increased the pupal volume, decreased pupal oxygen consumption, and reduced the pupal mitochondrial mass. These early-life effects were translated into sexually dimorphic effects on adult lifespan. Specifically, larval GALGLU consumption extended the lifespan of females when challenged with an obesogenic adult diet, whereas it reduced lifespan in males. To identify molecular correlates of the female-specific benefit, we profiled transcriptomes and lipidomes. Notably, larval GALGLU induced later-life transcriptional activation of cuticular hydrocarbon (CHC)-synthesizing enzymes, including the diene-producing desaturase Fad2, without changes in the monounsaturated fatty acid (MUFA)-producing desaturase Desat1, indicating increased MUFA demand without increased supply. Lipidomic analysis revealed decreased MUFA-containing and increased polyunsaturated fatty acid (PUFA)-containing glycerophospholipids. These data suggest that enhanced CHC biosynthesis depletes cellular MUFAs, driving compensatory incorporation of PUFAs into glycerophospholipids. Concluding, early-life galactose and glucose co-consumption programs sexually dimorphic lifespan, specifically by counteracting the lifespan-shortening effects of obesogenic diets in adult females, and redirects adult female lipid metabolism toward a PUFA-enriched glycerophospholipid profile.

Obesity and aging are converging health challenges, contributing to morbidity in older populations. However, the specific contribution of age to susceptibility to obesity is unclear. This study examined the impact of age on susceptibility to diet-induced obesity (DIO) and calorie restriction (CR) in male mice. Young (2-3 months) and old (17-24 months) lean C57BL/6J male mice were fed a standard chow diet (CD) or a high-fat diet (HFD) for 28 days, then underwent 18 days of CR. We monitored body weight, body composition, energy intake and expenditure, glucose tolerance, and gene expression in metabolically relevant tissues. HFD-fed old mice exhibited more fat mass gain but, surprisingly, protection from glucose intolerance. In comparison, young controls exhibited resistance to DIO due to reduced calorie storage efficiency. Gene expression analysis suggested reduced plasticity and lipid turnover in visceral adipose tissue but increased subcutaneous adipose tissue plasticity in old mice. The increased energy storage did not protect old mice from body weight loss following CR. Old mice exhibit increased susceptibility to DIO due to near optimal efficiency storing calories as fat. This susceptibility correlates with increased energy storage efficiency and the absence of energy demanding anabolic processes, like lean mass accrual, exhibited by young mice. Despite increased predisposition to obesity, lifelong leanness confers resilient glycemic control to old mice, emphasizing the importance of maintaining a healthy body weight and dietary habits throughout life to mitigate age-related metabolic risks.

Interventional therapy and surgery play important roles in the treatment of various diseases, but they cause varying degrees of vascular injury. Currently, the side effects are often overlooked. Here, we observed abnormal nuclear morphology (nuclear dysmorphism) and vascular aging in injured human and rodent arteries. Platelet-derived microvesicles (PMVs) adhere to injured blood vessels, leading to nuclear dysmorphism and cell senescence in vascular smooth muscle cells (VSMCs). This occurs because PMV adherence reduces intracellular Zn2+ levels, which impairs Zn2+-dependent processing of prelamin A by the enzyme ZMPSTE24. Consequently, prelamin A accumulates in VSMCs, contributing to the observed nuclear dysmorphism and cell senescence. RNA sequencing and loss-of-function assays revealed that Zinc transporter solute carrier family 39 member 4 (SLC39A4, also called ZIP4) deficiency accounts for the decreased Zinc concentration. Consistently, Zmpste24+/- and Zmpste24-/- mice displayed significant cumulative prelamin A, deteriorated nuclear dysmorphism and vascular aging. Whole genome bisulfite sequencing (WGBS) and bioinformatic analysis illustrated that demethylation of genes within Lamina-associated domains (LADs) participates in nuclear dysmorphism and cell senescence. Of note, Zinc supplementation, especially using platelet membrane-coated Zn-MOF nanoparticles, robustly alleviated nuclear dysmorphism and vascular aging. Our data established a novel and significant role of pMVs/ZIP4/zinc/prelamin A axis in promoting nuclear dysmorphism and vascular aging after injury.

Epigenetic clocks are commonly used aging biomarkers based on DNA methylation that predict long-term morbidity and mortality risk. Increased cellular senescence with age is also posited to contribute to age-related disease and mortality. However, prior studies have found that existing epigenetic clocks show inconsistent associations with cellular senescence and no reductions after senolytic treatment. We hypothesize this reflects that senescence-related CpGs are a small proportion of age-related CpGs, and that an epigenetic clock focused on a core senescence signal conserved across different cell types and different senescence inducers would be a better tool for monitoring senescence and senolytic treatment compared to traditional epigenetic clocks. In our study, we find that senescence, age and mortality risk intersect at a small subset of the DNA methylome (9363 CpGs out of 396,333 analyzed; 2.4%). Utilizing these CpGs, we generated three different epigenetic clocks trained to predict invitro senescence, age, and mortality, respectively. Surprisingly, all three of these predictors stayed the same or even accelerated after senolytic treatment in both invivo and invitro data. Our findings not only call into question whether cellular senescence can be captured by DNA methylation but also challenge the assumption that aging biomarkers decrease after geroscience interventions.

ABSTRACTAging impacts immune function, but the mechanisms driving age‐related changes in immune cell subsets remain unclear. To explore age‐dependent changes in immune cell populations, we analyzed human peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20–82 years using a 36‐color spectral flow cytometry panel focused on T cells. We identified a unique population of memory CD8 T cells, which lack CXCR3 and produce a Th2‐like cytokine response, and accumulate with age. We discovered an age‐dependent bias in naïve CD8 T cells toward Th2 cytokine production, accompanied by transcriptional and epigenetic changes supporting this phenotype. Moreover, health outcome association analysis linked the accumulation of these unique CXCR3‐ central memory CD8 T cells to asthma, chronic liver conditions, and type 2 diabetes. Together, our results support the model that an age‐dependent drift in epigenetic regulation toward a Th2‐like phenotype drives a pathogenic Th2‐like immune population.

ABSTRACTAging is the primary risk factor for numerous chronic diseases, making the identification of safe and effective anti‐aging strategies a critical focus in biomedical research. Heterochronic parabiosis by blood exchange shows that the exchange interaction between young and old plasma can exert anti‐aging effects through exchange of bloodborne factors. However, the limited plasma source greatly affects clinical translation. Here, we demonstrate that periodic therapeutic phlebotomy in D‐galactose‐induced aging models exerts significant and comprehensive anti‐aging effects, which is reflected by a notable improvement in aging‐associated behavioral deficits and neurogenesis, a significant decrease in the level of circulating senescence‐associated secretory phenotypes, and an obvious mitigation of aging‐associated structural degradation and molecular alterations within the muscle, bone, liver, kidney, and nervous systems. Mechanistically, periodic therapeutic phlebotomy induces bone marrow microenvironment restoration through functional rescue of mesenchymal stem cells and endothelial cells, thereby reestablishing balanced hematopoietic homeostasis. This hematopoietic revitalization subsequently drives systemic improvements in peripheral blood composition and function. In conclusion, our work provides preliminary evidence suggesting that periodic therapeutic phlebotomy exerts anti‐aging effects by restoring bone marrow function and mitigating aging phenotypes, subsequently driving peripheral blood functional restoration. Given its technical simplicity and safety profile, this periodic therapeutic phlebotomy strategy will hold potential to pave the way for clinical translation.