Reviews & Analysis

Skeletal muscle is a highly heterogenous tissue that comprises multiple cell types. Leveraging single-cell and single-nucleus experiments, we systematically mapped the cellular and molecular changes across different skeletal muscle compartments with age. We identify neuromuscular-junction accessory nuclei that may be pivotal in mitigating denervation and uncovered differences between myofiber and myonucleus aging.

The advent of plaque-clearing antibodies to the amyloid-β as the first disease-modifying treatment for Alzheimer’s disease will change the course of this disease, the most common type of dementia. Related progress will gradually alter the trajectory of human aging.

Our analysis of the spatiotemporal transcriptional features of human ovarian aging at the single-cell level identified the DNA damage response as a fundamental attribute in oocyte senescence. FOXP1, a gatekeeper both in granulosa and in theca and stroma cellular senescence, can be activated by quercetin treatment to delay ovarian aging.

Wu et al. explore vaccine strategies targeting age-related diseases, as well as senescent cells specifically, as potential underlying drivers of aging itself. They discuss challenges faced in clinical trials, as well as further optimizations required to increase therapeutic efficacy.

Staging Alzheimer’s disease on the basis of the disease’s biological underpinnings might help with stratification and prognostication, both in the clinical setting and in clinical trials. We propose a staging model based on only five biomarkers, which are related to amyloid-β and tau pathologies in different ways and can be measured with a single sample of cerebrospinal fluid.

Xu and colleagues used partial OSKM reprogramming in aged mice to drive cell-type proportions of the subventricular zone to more youthful levels, which equates to qualified rejuvenation of a neurogenic niche that is defined, in part, by restoration of neuroblast levels.

Intensive blood pressure control has been suggested to reduce the risk of adverse cardiovascular events. However, the effect of intensive blood pressure control on cardiac conduction system disease has not been clarified. Our study in older patients with hypertension identified no effect of intensive blood pressure control on cardiac conduction system diseases.

After discovering the sensitivity of the adrenal zona reticularis region to aging, we found that low-density lipoprotein receptor (LDLR) deficiency hampers both cholesterol uptake and dehydroepiandrosterone sulfate (DHEA-S) production. This finding reveals the cellular basis for age-related adrenal insufficiency and provides insights for the development of interventions to delay endocrine and systemic aging.

Epidemiological studies reveal a correlation between hearing loss and the development and progression of Alzheimer’s disease (AD), but the underlying causal mechanisms remain unclear. A study now provides experimental evidence that hearing loss can promote AD via the growth differentiation factor 1 (GDF1) pathway, which may aid in developing potential AD therapeutic strategies.

On 29–30 November 2023, the inaugural Global Healthspan Summit, convened in Riyadh by the nonprofit Hevolution Foundation, provided a dynamic platform that united experts from diverse sectors to foster collaborative discussions on aging research, innovative healthcare strategies and the healthspan ecosystem. This Meeting Report encapsulates the multifaceted insights that were garnered from the perspectives of science, economics and society.

The extracellular matrix is an essential component of the tumor microenvironment and affects cancer progression. Weeraratna and colleagues have now uncovered that age-related reductions in the level of hyaluronan and proteoglycan link protein 1 (HAPLN1) stimulate neoangiogenesis and compromise the vascular integrity of intratumoral blood vessels. These biological modifications converge to fuel distant melanoma metastasis.

Tissue mosaicism, driven by somatically acquired changes, is an emerging hallmark of aging. This Review coalesces recent discoveries from the hematopoietic system to integrate this phenomenon into the current framework of stem cell aging.

de Luzy et al. review recent work exploring the induction and functional consequences of neuronal senescence in aging and neurodegenerative disease, and discuss the potential of modeling neuronal senescence with pluripotent stem cell models.

Suda and colleagues explore the enduring consequences of plasma membrane injury in budding yeast and mammalian cells. Their findings highlight that membrane damage induces irreversible cell-cycle arrest and premature cellular senescence, whereas upregulation of plasma membrane repair suppresses them.

Our study demonstrates how clinical data can be used to build machine-learning models to predict the risk of Alzheimer’s disease (AD) onset and can be integrated with knowledge networks to gain insights into the pathophysiology of AD, with a focus on a better understanding of disease sex differences.

Amor and colleagues previously developed chimeric antigen receptor (CAR) T cells that can target and eliminate senescent cells. The utility of these senolytic CAR T cells is now expanded to show that they can combat age-related metabolic dysfunction, and that they can be used prophylactically and have effects that persist for months, thus opening the door to the development of long-term senolytic approaches.

Using a data-driven proteomics strategy from a prospective community-based cohort with long-term follow-up, this study reports that plasma levels of glial fibrillary acidic protein (GFAP) can predict the risk of dementia, even 15 years before disease diagnosis. Our findings have important implications for early screening and interventions for dementia.

Using a multi-omics strategy, we uncovered location- and sex-specific aging heterogeneity of the large intestine in monkeys and identified a range of potential gut aging regulators. We explored the roles of several regulators in intestinal function and lifespan in Caenorhabditis elegans. Finally, we investigated potential links between gut aging and colorectal cancer.

Ying et al. integrate Mendelian randomization into epigenetic clock making and pioneer a strategy to develop aging biomarkers with stronger causal ties to healthspan. They distinguish signs of aging-related molecular damage from responses to it that might signal resilience.

Proteomics analysis of cerebrospinal fluid (CSF) from individuals with Alzheimer’s disease (AD) identified five subgroups with distinct underlying mechanisms and genetic risk profiles. These subtypes might be a step forward in realizing personalized treatment for AD.