Reviews & Analysis

Tagmentation-based methylation sequencing (TIME-seq) is an efficient and cost-effective solution for measuring and generating epigenetic clocks. We applied TIME-seq to over 2,800 mouse and human DNA samples to produce clocks that demonstrate accuracy and robustness; the method also outperforms conventional methods in speed and cost. The simple and practical design of TIME-seq facilitates large-scale epigenetic clock analysis, which makes it a valuable tool for advancing aging research.

Oleson et al. tackle the enduring question of the extent to which transient events during development shape our outcomes by studying the effects of early-life exposure to oxidative stress. They find that a cascade of changes initiated by the epigenetic-modifier COMPASS complex manifests in rearrangements in lipid metabolism in adulthood, which confers broad protection against amyloid-induced proteotoxicity.

Two recent studies discover a scaling law of mammalian lifespans: the speed at which DNA methylation drifts from a youthful state strongly associates with maximum lifespan.

Cipriano et al. review recent progress in using epigenetic reprogramming to combat age-related deterioration at the cellular, tissue and organismal level, discussing reprogramming strategies and mechanisms, as well as remaining challenges in the field.

This Perspective describes and discusses the Information Theory of Aging, which proposes that aging primarily stems from the loss of youthful epigenetic information that can be restored via epigenetic reprogramming to heal injury and reverse aging.

Preclinical models are central to aging research. Yet, these models often lack key features of female humans. Here, the authors discuss shortcomings in the study of female aging and share opportunities for closing the gap in our understanding of sex-dependent aging trajectories.

Targeting tau in addition to amyloid-β could be the next phase of disease modification in Alzheimer’s disease. The TANGO trial of gosuranemab, which binds the tau N terminus, affected neither clinical outcomes nor brain levels of aggregated tau. The results highlight the importance and challenge of reducing aggregated tau.

In vivo reprogramming by expression of the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM factors) has been associated with early mortality and cancer. We report that these adverse effects are associated with liver and intestinal dysfunction. Strategic control of OSKM expression in these organs through a newly developed transgenic mouse model reduced adverse effects. Our model yields valuable insights into the potential of in vivo reprogramming for rejuvenation and regeneration.

On 22 March 2023, the Geroscience Translational Research & International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met in Toulouse, France to discuss avenues to foster the development of intrinsic capacity and frailty clinical trials under a geroscience perspective. A synthesis of these discussions and a set of recommendations are presented in this Meeting Report.

Senescent cells in the brain contribute to age-related neurodegeneration. Analysis of SARS-CoV-2 infection in human brain organoids, animals and post-mortem brain samples from patients with COVID-19 reveals virus-induced senescence. Pharmacological senolytic treatment following SARS-CoV-2 infection improves COVID-19 neuropathology and could help to protect people from long COVID.

Intrinsic capacity (IC) — a metric that reflects the composite of a person’s physical and mental capacities — varies across adulthood and between individuals of the same age. People with an IC below the tenth percentile suffer from a high burden of diseases, frailty, disabilities and recent falls.

To build health equity for an aging world, research at the intersections of biology, toxicology and the social and behavioral sciences points the way: to promote healthy aging, focus on the environment.

Epigenome deregulation is considered a hallmark of aging; however, the function of the alteration of DNA methylation in aged tissues is a long-standing question. Hong and colleagues reveal the mechanism and consequences of DNA methylation loss at heterochromatin regions in aged hematopoietic stem cells.

Female fecundity decreases one to two decades before the menopausal transition. A study by Zhang et al. now identifies aging-related decline of the polyamine spermidine as a crucial bottleneck for oocyte quality. Supplementation with spermidine rejuvenates oocytes in vitro and in vivo, and leads to improved fertility of middle-aged female mice.

Cognitive frailty (CF) is the complex and intertwined co-occurrence of physical frailty and cognitive decline. Untangling the interplay between these two domains and correctly diagnosing CF in the clinic is vital for early diagnosis and intervention.

Human aging is associated with increased rates of many cardiac diseases and tissue remodeling. However, disentangling the mechanisms that underlie normal heart aging from disease processes is challenging. A study now addresses this gap by investigating healthy primate cardiac aging and provides evidence that SIRT2 signaling may regulate cardioprotective effects.

Plants have an additional organelle to animals (the chloroplast), which means that they have a greater repertoire of protein homeostasis (proteostasis) mechanisms. We find that chloroplast proteostasis components prevent aggregation of a pathogenic fragment of human huntingtin expressed in plants, which reveals a potential avenue for therapeutic intervention in human proteinopathies.

Parkhitko et al. discuss combinatorial approaches targeting underlying mechanisms of aging across species and describe frameworks to analyze these interactions and their cross-species translational potential.

A recent publication in Nature Aging suggests that DOPA decarboxylase may serve as an emerging biomarker that can identify neurodegenerative disorders that are characterized by dopaminergic cell loss. Here we discuss how this finding can assist clinicians and researchers in the differential diagnosis of individuals who present with parkinsonism or cognitive decline.

Senescent cells accumulate with age and promote tissue decline. A broad genomic screen reveals that senescent cells can be eliminated from aged mice by interfering with their unique secretory program. Reducing the capacity of the endoplasmic reticulum by inhibiting the YAP–TEAD complex sensitizes senescent cells to apoptosis.