Reviews & Analysis

Lee and colleagues reveal a previously unrecognized population of astrocytes in the aged brain with disrupted proteostatic signaling that generates defects in astrocyte morphology, protein trafficking and synapse maintenance in the aging hippocampus.

The authors discuss how adopting a complex systems perspective is a crucial step in advancing our understanding of the aging process and requires fundamental alteration of the questions being asked and the methods used to answer them.

Global measures of the rate of aging can identify individuals who age faster than average and are at increased risk of adverse outcomes. Combining information on multiple physiological measures collected over time generated a global measure of aging that strongly predicted changes in physical and cognitive function.

Epigenetic clocks based on DNA methylation are widely used aging biomarkers, but their utility is limited by technical noise. A method based on principal component analysis produces high-reliability clocks for applications such as longitudinal studies and intervention trials.

Genetic variation linked to lower levels of soluble ST2, a decoy cytokine receptor for IL-33, may protect against Alzheimer’s disease in women carrying the APOEε4 allele by increasing microglial plaque removal. This discovery advances our understanding of the immune system’s role in Alzheimer’s disease and underscores the importance of sex-specific disease processes.

The microenvironment can regulate adult stem cell function during tissue homeostasis and regeneration, but whether and how this is altered in aging is unclear. Ichijo et al. find that increased dermal stiffness, as a result of vasculature atrophy, activates cation channel PIEZO1, leading to interfollicular epidermal stem cell dysregulation.

Muscle function decreases with age, and there are few preventative treatments. Zhang et al. find that different cell types in aging muscle express different senescence markers, giving insight into the complexity of senescence biology. They also show that aspects of muscle aging can be improved with senotherapeutic intervention.

Transcription factors can control cell identity and function in health and disease. However, how they do so during aging is incompletely explored. Maity and colleagues identify age-related changes in gene regulation by analyzing the expression patterns of transcription-factor target genes in single-cell transcriptomics data.

Compromised clearance of dysfunctional mitochondria, through the process of mitophagy, has garnered attention as an essential contributor to aging and neurodegeneration. Schmid and colleagues¹ reveal that genetic enhancement of mitophagy via neuronal overexpression of BNIP3 alleviates brain aging and prolongs healthspan in fruit flies.

Tau neuropathology is a defining feature of Alzheimer’s disease. For decades, its progression throughout the cortex has been captured post mortem using Braak stages. A new study replicated Braak staging in living patients using positron emission tomography, showing associations with other biomarkers and clinical deficits.

Whether and how cognitive training may be used to improve cognitive functions in older age remains incompletely explored, and existing studies have yielded inconsistent results. Here, the authors argue that emerging technologies can transform the field of cognitive enhancement by enabling personalized strategies for cognitive enhancement in older adults.

Older adults from long-term care facilities who had been infected with COVID-19 during the first wave of the pandemic were found to have robust cellular and humoral responses to SARS-CoV-2 spike protein. Importantly, serostatus did not affect humoral immunity to influenza or other respiratory syncytial viruses.

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.