Volume 3 Issue 8, August 2023

Han et al. provide a substantial contribution to our limited comprehension of the mechanisms of aging in adipose tissue. They show that, with age, increased levels of adipose CRTC2 decrease the breakdown of branched-chain amino acids and activate mTORC1. This in turn leads to increased levels of senescence-associated secretory phenotype factors, which promotes senescence and adipose dysfunction.

Neuronal aging is highly associated with misfolded protein aggregates that predispose to neurodegeneration, but the cellular factors that are involved in removing misfolded proteins are yet to be identified. In this issue of Nature Aging, Li and colleagues identified LONRF2 as an important player in protecting aging neurons against the accumulation of protein aggregates.

We treated aged monkeys with a dose of the longevity factor klotho, which is known to increase synaptic and cognitive functions in mice. We found that a relatively low dose of klotho enhanced cognition in aged monkeys. These findings are important because they suggest that klotho replenishment could prove to be therapeutic in aging humans.

By applying deep molecular profiling to our long-term mouse parabiosis model, we reveal reduced epigenetic age in old mice that shared circulation with young mice. The rejuvenation effect is sustained at two months after detachment, leading to lifespan extension and improved physical function, and is associated with rejuvenated transcriptomic signatures.

Our understanding of the genetics that underlies healthy aging can be improved by integrating complementary traits related to chronological and biological aging. We present a multitrait genome-wide association study that reflects the genetics of a broad healthy aging factor and use genetics methods to investigate potential therapeutic relationships among various drug targets.

High-throughput analysis of cellular landscapes is an important tool to decipher the molecular mechanisms driving aging and disease. Here, Singh and Benayoun discuss key considerations in the design and analysis of omic data to gain robust and reproducible insights into the aging process.

Cognitive dysfunction in aging is a major biomedical challenge without medical therapies. Here, Castner et al. show that longevity factor klotho enhances cognition in aged nonhuman primates, increasing its relevance for a therapeutic path to humans.

De-Souza, Thompson and Taylor demonstrate that pathogen-associated odorants can activate the UPR cell non-autonomously in C. elegans via neuronal TGF-β signaling, leading to extended lifespan and enhanced clearance of toxic proteins.

Heterochronic parabiosis ameliorates age-related diseases in mice, but how it affects epigenetic aging and long-term health was not known. Here, the authors show that in mice exposure to young circulation leads to reduced epigenetic aging, an effect that persists for several months after removing the youthful circulation.

Shen, Gao and Luo et al. show that the epigenetic regulator Cxxc1 plays an important role in maintaining homeostasis and function of group 3 innate lymphoid cells that are involved and key in regulating intestinal immunity during aging.

Adipose tissue has an important role in metabolic homeostasis and undergoes age-related changes contributing to metabolic decline, via mechanisms that remain incompletely explored. Here the authors show that Crtc2 deficiency in adipocytes protects against age-related hyperactivation of the BCAA–mTORC1 axis and metabolic alterations.

Many age-related disorders, such as neurodegenerative diseases, are associated with protein misfolding. Here, the authors identify LONRF2 as a protein quality control ubiquitin ligase that is expressed in neurons and ubiquitylates misfolded TDP-43 and hnRNP M1 and show that loss of Lonrf2 in mice results in late-onset motor neuron degeneration, whereas its ectopic expression partially rescued the phenotypes observed in motor neurons derived from patients with amyotrophic lateral sclerosis.

Using a multivariate genome-wide association study approach, the authors identified 52 genetic variants associated with aging-related traits, many of which are promising cardiometabolic targets that could promote healthy aging and inform future interventions.