Reviews & Analysis

High-affinity tau-PET was used to apply the Braak neuropathological staging system for Alzheimer’s disease in vivo. Tau-PET can be used to stage Alzheimer’s disease from presymptomatic to clinical dementia phases in people, while also providing a framework to model the natural history of Alzheimer’s disease using biomarkers.

Aging is accompanied by a gradual decline of cell proliferation potential. FOXM1 is a transcription factor involved in cellular proliferation and cell cycle progression. Ribeiro et al. show that cyclic expression of a truncated form of a FOXM1 transgene in vivo can delay senescence-associated progeroid and natural aging phenotypes in mice.

Forkhead box protein M1 (FOXM1) is a transcription factor with pleiotropic roles in cell proliferation, differentiation and senescence. This study shows that cyclic induction of a FOXM1 transgene in mouse models of Hutchison–Gilford progeria and natural aging significantly extends healthspan and ameliorates the senescence-associated histopathology driven by repression of endogenous Foxm1.

Mass spectrometry analysis of mouse cerebrospinal fluid revealed that several proteins change in abundance or structure during aging. The six proteins that show the most robust structural changes are associated with cognition or Alzheimer’s disease in human cerebrospinal fluid, thus revealing candidate diagnostic biomarkers and potential therapeutic targets.

Public health policies recommend maintaining a body mass index below 25, after which individuals are considered to be overweight or obese. A new study looked at optimal BMI in adults in China in their ninth decade or older, and concludes that these recommendations need to be revised upwards in this age group.

Neurodegenerative diseases, including Parkinson’s disease, are linked to the accumulation of defective mitochondria in the brain and to microbial dysbiosis in the gut. However, the interplay between these factors is incompletely understood. Fedele et al. reveal how gut mitochondrial dysfunction activates intestinal inflammation to drive neurodegeneration in a Parkinson’s disease model.

In a sample of >19,000 older adults, the presence of depressive symptoms was associated with adverse medical outcomes over five years, including persistent physical disability, cancer and major bleeding episodes. Certain depression trajectories were associated with distinct health conditions. Systematic assessment of depressive symptoms may facilitate early identification of at-risk populations.

Frailty is an important age-related prognostic for mortality, and little is known about its immune landscape. Luo et al.¹ use single-cell profiling to gather a comprehensive understanding of immune changes that happen from birth to old age, and provide new insights into the often-overlooked state of frailty.

Apolipoprotein E (APOE) is an important regulator of lipid metabolism and is genetically associated with longevity and age-related diseases such as Alzheimer’s disease. However, the molecular mechanisms that link APOE and aging are incompletely understood. Now an article in Nature Aging reveals that nuclear APOE promotes senescence by destabilizing heterochromatin.

While investigating sex differences in T cell aging, Mkhikian et al. identified a role for excessive IL-7 signaling and N-glycan branching in age-related T cell dysfunction in women and female mice. These findings point to the increasingly recognized importance of the effects of biological sex on immune aging, and delineate new targetable pathways in age-related immune dysfunction.

In cohorts of young and older adults who were comprehensively phenotyped, Janssens and colleagues traverse an important translational gap by providing compelling evidence for the purported link between elevated NAD⁺ levels and the healthy aging muscle phenotype in humans.

This Review provides an update on the pleiotropic effects of mitochondria in aging and discusses how defects in mitochondrial stress pathways contribute to the decline in cellular and systemic homeostasis during aging and age-related diseases.

Plant-based diets emphasizing healthful plant foods were associated with a lower risk of mortality among older adults, whereas a plant-based diet rich in less-healthful plant foods was related to a higher mortality risk. Thus, the quality of plant foods deserves attention in future plant-based dietary recommendations.

In cultured cells and in mice with accelerated aging, brief bursts of Yamanaka reprogramming factors reverse some molecular and functional deficits of aging without inducing pluripotency or teratomas. Browder et al. show that partial reprogramming regimens rejuvenate some tissues of physiologically aged mice without overt safety concerns.

Life expectancy is partially determined by an individual’s genetic make-up. Whole-exome sequencing analysis of >350,000 UK Biobank participants revealed that protein-truncating variants in four genes, BRCA1, BRCA2, ATM and TET2, are negatively associated with human lifespan. Phenome-wide analyses confirm roles for these genes in cancer and clonal hematopoiesis.

Vascular senescence has been implicated in atherosclerosis. By characterizing SNPs in the p16-encoding CDKN2A/B locus, a new study in Nature Aging identifies CUX1 as a binding protein of an atherosclerosis-associated functional SNP, which activates CDKN2A expression and senescence in endothelial cells, thus providing a mechanism of transcriptional senescence regulation.

Telomeres, the caps of chromosomes, shorten with age. Using qPCR, Nilhesh Samani, Veryan Codd and colleagues measured leukocyte telomere length in close to half a million individuals from the UK Biobank, confirming several previous associations. This dataset offers many new opportunities to explore associations between leukocyte telomere length and other traits relevant to human aging and health.

As the elderly population continues to grow exponentially, dry eye disease is becoming increasingly common. In this issue, Sasaki and colleagues identified a NAD⁺-regulated steroidogenic pathway in the eye that supports the normal function of meibomian glands, and show that increasing the availability of NAD⁺ can alleviate the dry eye phenotype of aged mice.

Countries are advancing retirement age as life expectancy advances. But increases in healthy life expectancy are not keeping pace with total life expectancy, lengthening the portion of life spent with disability and threatening the capacity of individuals to work longer. Now, a study forecasts healthy life expectancy for people in England in 2035.

Many aging-related traits share a common genetic component. How to disentangle it from trait-specific effects has remained largely unexplored. A new study in Nature Aging uses an analysis framework for isolating the shared genetic component in GWAS of aging-related traits, and identifies genomic loci that contribute to longevity.