Volume 5 Issue 2, February 2025

In mammals, the 5-methylcytosine epigenetic mark is mostly located in transposable elements, which are repetitive intragenomic parasites. In this issue of Nature Aging, Gorbunova and colleagues show that 5-methylcytosine levels in certain LINE1 retrotransposon loci highly correlate with age and the incidence of certain pathologies. Thus, LINE1 (the only known transposable element family capable of autonomous jumping in the human genome) serves as a suitable DNA template for accurately determining age and predicting disease.

Iltis, Moskalevska and colleagues investigate how the innate immune system regulates the age-related accumulation of senescent cells. They show that upregulation of the GD3 ganglioside-based immune checkpoint enables senescent cells to evade immune surveillance mediated by natural killer cells during aging, and that targeting GD3 is protective in age-related disease.

This study highlights the biological embedding of aggregate-level structural socioeconomic inequality and reveals its effect on brain volume and network dynamics, particularly in aging, Alzheimer’s disease and frontotemporal dementia. Through a comparative analysis between Latin America and the USA, the research highlights brain health disparities driven by structural inequality.

Single-nuclei multiomics analyses of ovarian tissue from young and reproductively aged individuals reveal mTOR signaling as an ovary-specific aging pathway and identify functional genetic variants associated with ovarian aging. This comprehensive atlas provides insights into molecular and genetic mechanisms of ovarian aging and potential therapeutic targets for reproductive longevity.

In January 2024, a Hevolution Alliance for Aging Biomarkers thinktank convened at Cold Spring Harbor to discuss the framework for creating an open and diverse data resource for developing reliable aging biomarkers. As the funding for this initiative has now been confirmed, we summarize recommendations and key milestones for its implementation.

Transposable elements activate during aging with negative consequences. Morandini et al. show that transposons show rapid loss of methylation in peripheral blood mononuclear cells during aging and that models trained on transposon methylation accurately predict age.

Using whole-exome sequencing followed by in vitro enzymatic assays, Chew, Liu, Li, Chung et al. identified rare protein-coding variants in GBA1 and SMPD1 that significantly associate with risk of Parkinson’s disease across cohorts of Asian descent.

This study identifies a novel immune checkpoint in senescent cells that is linked to the ganglioside GD3 and that contributes to the evasion of immune clearance by these cells and to aging and age-related diseases.

Lee et al. demonstrate that Ginkgolide B treatment extends lifespan and enhances healthspan in female mice, including a reduction in tumor incidence, enhancement in muscle quality and function and suppression of systemic inflammation and senescence.

The authors find that structural economic inequality is linked to reduced brain volume and connectivity in middle-aged and older adults across the Americas, more so in Alzheimer’s disease than in frontotemporal dementia. The findings emphasize the biological embedding of inequality in aging and dementia.

The molecular and cellular mechanisms underlying ovarian aging are incompletely understood. Here the authors provide single-nuclei RNA and ATAC-seq of human ovarian tissue from four young and four reproductively aged donors, revealing coordinated transcriptomic and epigenomic changes across cell types and highlighting a role for mTOR signaling in reproductive aging.

Using mouse and human plasma, Carver et al. identify factors that are altered with age and test which are reverted by a panel of genetic and pharmacological senolytic interventions in aged mice. They identify IL-23R as a senescence-associated, age-increased circulating biomarker.

Using small RNA sequencing data from aged human brain tissue, Vattathil, Gerasimov et al. uncovered genetic variants that influence microRNA (miRNA) expression and, by integrating genome-wide association study data, identified miRNAs linked to the etiology of psychiatric and neurodegenerative disorders.

Ryan and colleagues present multi-tissue, multi-omics, longitudinal datasets from the CALERIE phase 2 randomized controlled trial of caloric restriction in humans, providing a powerful resource for translational geroscience.