How to measure biological aging in humans
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Golgi-restored vesicular replenishment retards bone aging and empowers aging bone regeneration
Healthy aging is a common goal for humanity and society, and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration. However, the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive. Here, we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell (MSC) function and regeneration. Interestingly, replenishment of cell aggregates-derived extracellular vesicles (CA-EVs) rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5. Importantly, in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice, suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration. Collectively, our findings provide insights into Golgi regulation in stem cell senescence and bone aging, which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.
Single-cell immune aging clocks reveal inter-individual heterogeneity during infection and vaccination
Aging affects human immune system functionality, increasing susceptibility to immune-mediated diseases. While gene expression programs accurately reflect immune function, their relationship with biological immune aging and health status remains unclear. Here we developed robust, cell-type-specific aging clocks (sc-ImmuAging) for the myeloid and lymphoid immune cell populations in circulation within peripheral blood mononuclear cells, using single-cell RNA-sequencing data from 1,081 healthy individuals aged from 18 to 97 years. Application of sc-ImmuAging to transcriptome data of patients with COVID-19 revealed notable age acceleration in monocytes, which decreased during recovery. Furthermore, inter-individual variations in immune aging induced by vaccination were identified, with individuals exhibiting elevated baseline interferon response genes showing age rejuvenation in CD8+ T cells after BCG vaccination. sc-ImmuAging provides a powerful tool for decoding immune aging dynamics, offering insights into age-related immune alterations and potential interventions to promote healthy aging.
Reducing functionally defective old HSCs alleviates aging-related phenotypes in old recipient mice
Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit “younger” molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice. Thus, our study demonstrates the presence of “younger” HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.
Functional brain network dynamics mediate the relationship between female reproductive aging and interpersonal adversity
Premature reproductive aging is linked to heightened stress sensitivity and psychological maladjustment across the life course. However, the brain dynamics underlying this relationship are poorly understood. Here, to address this issue, we analyzed multimodal data from female participants in the Adolescent Brain and Cognitive Development (longitudinal, N = 441; aged 9–12 years) and Human Connectome-Aging (cross-sectional, N = 130; aged 36–60 years) studies. Age-specific intrinsic functional brain network dynamics mediated the link between reproductive aging and perceptions of greater interpersonal adversity. The adolescent profile overlapped areas of greater glutamatergic and dopaminergic receptor density, and the middle-aged profile was concentrated in visual, attentional and default mode networks. The two profiles showed opposite relationships with patterns of functional neural network variability and cortical atrophy observed in psychosis versus major depressive disorder. Our findings underscore the divergent patterns of brain aging linked to reproductive maturation versus senescence, which may explain developmentally specific vulnerabilities to distinct disorders.
Single-cell transcriptomic atlas of the human testis across the reproductive lifespan
Testicular aging is associated with declining reproductive health, but the molecular mechanisms are unclear. Here we generate a dataset of 214,369 single-cell transcriptomes from testicular cells of 35 individuals aged 21–69, offering a resource for studying testicular aging and physiology. Machine learning analysis reveals a stronger aging response in somatic cells compared to germ cells. Two waves of aging-related changes are identified: the first in peritubular cells of donors in their 30s, marked by increased basement membrane thickness, indicating a priming state for aging. In their 50s, testicular cells exhibit functional changes, including altered steroid metabolism in Leydig cells and immune responses in macrophages. Further analyses reveal the impact of body mass index on spermatogenic capacity as age progresses, particularly after age 45. Altogether, our findings illuminate molecular alterations during testis aging and their relationship with body mass index, providing a foundation for future research and offering potential diagnostic markers and therapeutic targets.
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