Volume 4 Issue 1, January 2024

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.

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.

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.

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.

DNA methylation rates correlate with maximum lifespan in mammals, but a precise relationship had not been defined. Here Crofts et al. develop a statistical framework to compare methylation rates at conserved age-related sites and find that methylation rates negatively scale with maximum lifespan in 42 mammalian species.

Tijms et al. identify five molecular Alzheimer’s disease subtypes typified by hyperplasticity, impaired immune activation, RNA metabolism, and choroid plexus or blood–brain barrier function. Subtypes may need tailored cures.

Using C. elegans, Oleson et al. demonstrate that developmental exposure to reactive oxygen species protects against amyloid toxicity later in life, mediated by disruption of the H3K4me3 epigenetic machinery through HSF-1-dependent shifts in lipid metabolism.

Li and Guo et al. demonstrate that epigenetic dysregulation of the MLL complex at promoters of particular age-dependent genes results in their transcriptional downregulation and subsequent age-related dysfunction of neural stem and progenitor cells.

Cikes et al. report dysregulation of glycerophosphocholine (GPC) metabolism in aged mouse muscle, which they functionally link to severe glucose intolerance. Correspondingly, muscle GPC levels are altered in both older adults and patients with type 2 diabetes.

To analyze neuronal aging in Huntington’s disease, Lee et al. perform direct neuronal reprogramming of longitudinally aged human fibroblasts, uncovering RCAN1 as a therapeutic target to promote neuronal resilience through chromatin reconfiguration.

Multiple lines of research show that NAD⁺ has an important role in ovarian aging; however, the role of NAD⁺ consumption during ovarian aging is incompletely understood. Here the authors study the role of the NADase CD38 to show that CD38 expression increases and NAD⁺ levels decrease with age in mice, and that CD38 deletion ameliorates ovarian aging.

Stitching together electronic health records with partial longitudinal coverage, Mendelson Cohen et al. use machine learning to untangle healthy aging from chronic disease, identifying markers of healthy aging and analyzing the heritability of longevity.

Isola, Ocañas et al. report age-related changes in the mouse ovarian transcriptome at single-cell resolution, demonstrating an increase in lymphocytes that corresponds to declines in collagen degradation and accumulation of multinucleated giant cells.