ABSTRACT Genetic trade‐offs can constrain life‐history evolution resulting in the evolution of ageing. Reduced insulin/insulin‐like signalling (rIIS) improves somatic maintenance and dramatically increases lifespan in Caenorhabditis elegans , but the effects on fitness are unclear. Here we used a novel experimental approach to show that, contrary to the prevailing paradigm, rIIS via daf‐2 RNAi during development can improve development, reproduction, survival, individual fitness, and population growth rate in the laboratory and semi‐natural conditions. However, developmental rIIS extends lifespan and improves fitness only in some temperatures, which explains why our results differ from previous findings. Furthermore, while developmental rIIS can improve a suite of life‐history traits in parents, it slows down offspring development. Finally, because rIIS interferes with environmental sensing and compromises adaptive developmental plasticity in response to stress, a central part of C. elegans life history in nature, the ability to sense the environment correctly during development comes at the cost of accelerated senescence. These results suggest the complexity of gene‐by‐environment interactions during development imposes constraints on molecular signalling networks leading to genetic trade‐offs across the life course that natural selection in late‐life is unable to resolve. However, these constraints can be resolved by artificially fine‐tuning gene expression at different ages.
ABSTRACT Aging is associated with functional decline and reduced regenerative capacity in the brain, is also the strongest risk factor for ischemic stroke, which remains a leading cause of mortality and long‐term disability worldwide, and is associated with impaired functional recovery. Here, we investigated whether short‐term partial cellular reprogramming through cyclic expression of Yamanaka factors (OSKM) in a Tet‐ON mouse model under Rosa‐26 promoter has any impact on ischemic damage in aged mice. To assess ischemic resilience, mice underwent permanent middle cerebral artery occlusion (pMCAo). Forty‐eight hours after ischemia, OSKM‐induced mice displayed significantly smaller damaged area compared with wild‐type controls, accompanied by improved neurological scores and enhanced performance in the tightrope test, suggesting preserved sensorimotor abilities. Notably, myelin integrity was preserved in OSKM‐treated mice, as shown by Black‐Gold staining and stable MAG and MBP expression, whereas wild‐type mice exhibited pronounced demyelination. Given the role of oligodendrocytes in myelin maintenance, we quantified the abundance of their different populations. OSKM induction significantly increased total oligodendrocytes (Olig2 + ) and oligodendrocyte precursor cells (PDGFRα + ) following ischemia, suggesting an enhanced reparative response. Moreover, partial reprogramming preserved neuronal density in the ischemic cortex and prevented the marked astrocytic activation observed in wild‐type mice, while microglial responses remained comparable across genotypes. These findings demonstrate that cyclic partial reprogramming in aged mice reduces ischemic damage, highlighting OSKM induction as a promising strategy for enhancing brain resilience during cerebrovascular accidents.
ABSTRACT Genome aging refers to age‐related acquisition and expansion of de novo mutations in somatic cells, and is now increasingly viewed as a central driver of organismal aging. Loss of X chromosome (LOX), the state in which one X chromosome (ChrX) is missing, represents the most common genetically inferred type of acquired mutation in women. Recent technological advancements, along with the growing availability of large‐scale cohorts for association studies, have provided powerful new insights into this phenomenon. The frequency and clone size of LOX increase significantly with age: with over 10% of women aged 55 years or older showing detectable LOX in blood. LOX preferentially affects the inactivated ChrX derived from either parent, or in some cases, affects the ChrX from one specific parent. Besides aging, the acquisition and expansion of LOX are shaped by factors related to ChrX itself, genome‐wide inherited and acquired variants, and lifestyle and environmental stressors. Due to the critical biological roles of ChrX, even in its inactive state, LOX impairs cellular functions and is strongly linked to hematological malignancies and a range of benign diseases. Understanding the mechanisms driving the causes and consequences of LOX may expand the sex‐biased genomic architecture of aging and uncover strategies for disease prevention in women. In this review, by integrating the most recent progress in LOX studies with unique biology of ChrX and perspectives from aneuploidy, we provide a synthesized and updated understanding of the rise, expansion and consequences of blood LOX, while also posing key questions for future research.
ABSTRACT Calcific aortic valve disease (CAVD) is an age‐associated valvular disorder in which calcification expands from discrete foci into adjacent tissue. We investigated whether mitochondrial‐derived vesicles (MDVs) released by human valvular interstitial cells (hVICs) exert pro‐calcific effects on recipient cells and how MDV release is regulated. Using ex vivo hemodynamic perfusion of human CAVD tissue, multi‐omics profiling, live‐cell single‐organelle tracking, MDV transfer assays, and in vivo Gas6 deletion, we found that calcifying hVICs hypersecreted MDVs that exerted pro‐calcific effects in recipient hVICs. High‐resolution imaging showed that mitochondria remodeled into donut‐shaped structures under pro‐osteogenic conditions; these structures served as physical platforms for MDV budding. Human CAVD valve tissues and hVICs treated with pro‐osteogenic medium also exhibited senescence‐associated features. Multi‐omics profiling identified growth arrest‐specific 6 (Gas6), a senokine, among 36 concordantly upregulated candidates. Functional analyzes showed that Gas6 promoted terminal MDV scission while leaving donut‐shaped mitochondrial precursor formation intact. Mechanistically, Gas6 promoted intracellular Ca 2+ accumulation, calcium/calmodulin‐dependent protein kinase II (CaMKII) activation, and dynamin‐related protein 1 (DRP1) phosphorylation at Ser616, supporting a Ca 2+ –CaMKII–DRP1 axis that facilitates terminal MDV scission. Pharmacological inhibition of CaMKII or DRP1 reduced MDV hypersecretion and subsequent recipient‐cell calcification, and Gas6 deletion in vivo attenuated valvular stenosis, calcification, and fibrotic remodeling. These findings identify Gas6‐dependent terminal MDV scission as a mechanism contributing to the intercellular propagation of valvular calcification in a CAVD context characterized by senescence‐associated features.
ABSTRACT Nicotinamide adenine dinucleotide (NAD + ) is an essential metabolite that regulates diverse cellular metabolic processes. Primary cilia, hair–like organelles on the cell surface, function as critical signaling hubs. Here, we demonstrate that cellular NAD + levels are key regulators of both primary cilia growth and lysosomal function in hypothalamic neurons. NAD + depletion induces ciliary shortening and diminishes lysosomal activity in a cilia–dependent manner. Mechanistically, the lysosomal repair complex protein CHMP4B translocates from periciliary satellites to lysosomes during lysosomal stress, a process impaired by ciliary dysgenesis. Disrupted lysosomal recruitment of CHMP4B leads to abnormal lysosomal Ca 2+ signaling and lysosomal dysfunction. Aged mice with hypothalamic NAD + deficiency exhibit shortened cilia and lysosomal stress phenotypes, both of which are restored by calorie restriction (CR). Moreover, CR improves aging–associated metabolic dysfunction, at least in part, through hypothalamic cilia–dependent mechanisms. These findings identify a primary cilium–mediated–NAD + signaling axis that maintains lysosomal homeostasis in hypothalamic neurons, the disruption of which drives metabolic aging.
