Aging Cell最新文献

The potential of proteomic aging clocks for obesity research, and the extent of nonlinearity in longitudinal associations between body weight and biological aging, remain underexplored. We investigated how BMI at ages 18 and ~60, as well as changes in BMI from age 18 to ~60, relate to downstream epigenetic and proteomic aging. We also examined nonlinearity and interactions in these associations. Analyses were conducted in 401 Finnish twins with up to nine self-reported or measured BMI values collected over 40 years. Olink proteomic and Illumina DNA methylation data were generated from blood drawn at the last BMI measurement. From these data, we derived four proteomic and five epigenetic age estimates and modeled BMI change over time using mixed-effects models. Generalized additive models were then applied to examine (1) nonlinear associations between BMI trajectories and biological aging, adjusting for chronological age, and (2) interactions of baseline BMI with BMI change and BMI at ~60 years. BMI at 18 and ~60 years old and changes in BMI were associated with increased biological aging for most aging estimates. We found statistical evidence of nonlinearity for about one-third of the significant associations, mostly observed for proteomic clocks. We further identified suggestive evidence for interactions between BMI at 18 years and BMI at ~60 years in explaining variability in two proteomic clocks (p = 0.07; p = 0.09). In conclusion, our study illustrates the potential of proteomic clocks in obesity research and highlights that assuming linearity in associations between BMI trajectories and biological aging is a critical oversight.

Adverse events across the life course have been linked to older biological ageing profiles. Whether these associations differ between males and females, and whether such differences depend on adversity occurring in childhood, adulthood or both periods, remains unclear. In 153,557 UK Biobank participants aged 40-69 years, we assessed associations of childhood and/or adulthood adversity with metabolomic ageing, frailty, telomere length and grip strength. Sex differences were evaluated using stratified analyses and sex-by-adversity interaction tests. Exposure to adversity in childhood and/or adulthood was reported by 64.6% of males and 69.6% of females. Childhood adversity was associated with multiple ageing markers primarily in females, including a metabolite-predicted age exceeding chronological age, greater frailty, shorter telomeres and weaker grip strength. Adulthood adversity was more strongly associated with certain ageing markers in males, particularly greater frailty and weaker grip strength. This divergence in sex-specific associations between childhood and adulthood exposure was consistent across several markers, with statistically significant sex-by-adversity interactions for frailty and grip strength. In this large, population-based sample, the timing of adversity, distinguishing childhood from adulthood, shaped whether females or males showed stronger associations with biological ageing markers. These findings suggest that sex differences in biological ageing profiles may partly reflect distinct sensitive periods of vulnerability, highlighting the importance of considering both sex and timing of exposure to adversity when examining links between adversity and biological ageing.

Aging 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.

Epigenetic remodeling is a hallmark of aging, yet which epigenetic layers are most affected during aging-and the extent to which they are interrelated-is not well understood. Here, we perform a comprehensive analysis of epigenetic aging encompassing 6 histone marks and DNA methylation measured across 12 tissues from > 1000 humans and mice. We identify a synchronized pattern of age-related changes across these epigenetic layers, with all changes converging upon a common set of genes. Notably, an epigenetic clock based on these genes can accurately predict age using data from any layer (Spearman ρ: 0.70 in humans, 0.81 in mice). Applying this "pan-epigenetic" clock, we observe that histone modification and DNA methylation profiles agree in the prediction of which individuals are aging more rapidly or slowly. These results demonstrate that epigenetic modifications are subject to coordinated remodeling over the lifespan, offering a unified view of epigenetic aging.

Centenarians exhibit remarkable longevity and compression of morbidity making them an ideal population for uncovering proteins associated with successful aging. Using proteomics, we characterized the immune and cardiometabolic profiles of centenarians' plasma from the SWISS100 cohort. We identified 583 differentially expressed proteins (DEPs) by centenarians when compared with hospitalized geriatric patients (age 80-90 years) and younger healthy participants (age 30-60 years). We replicated the association of 23 proteins with a standard set of aging proteins (APs) developed by the Targeting Aging with Metformin (TAME) consortium. By comparing the centenarian signature to an independent centenarian proteomics study, we identified 135 DEPs in both studies with identical aging directions, establishing a robust set of APs in centenarians. Applying fractional polynomial regressions, we uncovered proteins with linear and non-linear profiles associated with age and identified a subgroup of 37 proteins with a younger signature in centenarians. Protein-protein interaction and pathway enrichment analyses of 37 proteins point to programmed cell death, metabolic enzyme pathways, regulation of extracellular matrix stability, immune and inflammatory responses, and neurotrophic signaling pathways. This novel approach to aging research has uncovered new proteins and pathways, which may present promising targets to understand processes associated with longevity and healthy aging.

Senescent fibroblasts accumulate in the connective tissue of all organs and promote organ aging and aging-related diseases. The underlying mechanisms for the accumulation of senescent fibroblasts are poorly understood. Natural killer (NK) cells of innate immunity play a critical role in the removal of tissue resident senescent cells. We here show that NK cells from old adults and old mice fail to efficiently remove senescent fibroblasts. This is due to severely reduced perforin and granzyme B release from aged NK cells where perforin is responsible for inducing holes in the membrane of senescent fibroblasts through which granzyme B enters enforcing cell death of senescent fibroblasts. We demonstrate elevated activation of the small Cdc42 Rho GTPase in aged NK cells to be responsible for the disruption of the microtubular organization which is essential for the proper release of perforin and granzyme B and for energy homeostasis. Attenuation of the elevated activity of Cdc42 in aged human NK cells with CASIN, a small molecule Cdc42 inhibitor, rebalances Cdc42 activity to a young level. Rebalancing of Cdc42 restores proper perforin and granzyme B release and attenuates reduced ATP levels in aged NK cells resulting in an attenuated "youthful" cytotoxicity of aged NK cells against senescent cells. Collectively, we identified a previously unreported molecular mechanism underlying functional impairment of NK cells from older adults. In perspective, our data hold promise to develop novel strategies against age-related disorders driven by tissue-resident senescent fibroblasts.

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to dietary metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and metabolic dysfunction-associated steatotic liver disease (MASLD) progression.

Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity-seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux-resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (Lin-BM), and in hematopoietic stem and progenitor cells (HSPCs), immunophenotypically lineage marker negative (Lin-) Sca1+ cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and Lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSPCs during aging. ScRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin-BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells, as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this work should serve as a useful resource for understanding and therapeutically targeting the aged hematopoietic system.

Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight necessitating euthanasia. In the livers and kidneys of these animals, we observe significant increases in lipid droplet accumulation, as well as changes in mitochondrial morphology in the livers that are associated with mitochondrial stress. Thus, partial chemical reprogramming may induce mitochondrial stress and lead to significant lipid accumulation, which may cause toxicity and hinder the rejuvenation of cells and tissues in aged mammals.

To maintain protein homeostasis, which is essential for health, animals have developed complex protective mechanisms against various acute and chronic stresses. However, the coordination of responses to these protein stresses, especially their age-dependent changes, is not well understood. HSF-1 is a key regulator of protein homeostasis. Our study identifies PBS-7, a proteasome subunit, as its crucial regulator. In aged C. elegans, decreased PBS-7 binding reduces proteasome-mediated degradation of HSF-1. The increase in HSF-1 enhances responses to chronic stresses, like accumulating protein aggregates, by upregulating heat shock proteins (HSPs) and autophagy genes. Meanwhile, the upregulated HSPs suppress the activation of HSF-1 upon acute stress, such as heat shock. Our findings reveal a mechanism that coordinates responses to acute and chronic protein stresses and highlights an adaptation prioritising protection against increasing protein aggregates in ageing.