Volume 4 Issue 3, March 2024

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.

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.

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.

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.

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.

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.

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.

Plasma membrane damage (PMD) can induce cell death or be repaired, whereas other cell fates are not well explored. In this study, the authors found that PMD induces senescence in yeast and human fibroblasts in a manner that is distinct from DNA damage-dependent senescence. They present transcriptomic data suggesting that this PMD response may explain the origins of senescent cells near cutaneous wounds.

The accumulation of senescent cells drives age-related diseases. In this study, the authors show that senolytic CAR T cells can rejuvenate metabolic function and fitness in old mice and that a single dose is sufficient to lead to long-term preventive effects.

Older age is associated with worse outcomes for patients with melanoma, and the underlying mechanisms are incompletely understood. Here the authors show that the loss of HAPLN1 in aged skin fibroblasts drives melanoma progression by increasing ICAM1 and angiogenesis. Blocking ICAM1 shrinks tumors, suggesting potential for age-specific melanoma therapy.

Aging is a risk factor of Parkinson’s disease (PD). Adams, Song et al. present a multiomics analysis of the human midbrain showing age-induced changes in genes associated with glial function, with further alterations of oligodendrocytes in PD.

Identifying individuals at risk of developing Alzheimer’s disease is an important task. Here Tang et al. leverage electronic health records to predict Alzheimer’s disease onset, and utilize knowledge networks to prioritize shared genes behind the clinical data as well as facilitate contextualization based on sex.

Wang et al. generate a single nucleus-resolved transcriptomic atlas of primate adrenal aging, with which they demonstrate regional changes in adrenal aging, and establish the role of LDLR in impeding cholesterol uptake and DHEA-S production in aging.

Using a multi-omics approach, Wang et al. explored sex-specific and region-specific patterns of intestinal aging in non-human primates, identifying regulators with conserved functions in Caenorhabditis elegans intestinal aging, in colitis in mice and in patient colorectal cancer samples.