Volume 6 Issue 1, January 2026

Biological aging clocks predict health outcomes, including morbidity and mortality, more accurately than chronological age alone, yet defining true biological age remains contentious. We propose ‘risk-equivalent’ age as an operationally defined metric that reflects an individual’s position on a continuum of clinically meaningful risk. Reconceptualizing biological age as a dynamic, risk-based vital sign may facilitate the use of aging clocks in clinical practice.

As Nature Aging celebrates its fifth anniversary, the journal asks some of the researchers who contributed to the journal early on to reflect on the past and the future of aging and age-related disease research, the impact of the field on human health now and in the future, and what challenges need to be addressed to ensure sustained progress.

For Nature Aging’s fifth anniversary, we acknowledge the essential work that is done by our colleagues, without which Nature Aging’s monthly publication would not be possible. We speak with some of our internal colleagues about the process of making a journal every month. Rebecca Roberts is a production editor at Springer Nature, Mark McGranaghan is a senior sub editor, Lauren Snape is an art editor and Amanda Karmolinski is a senior editorial assistant. In this Q&A, Rebecca, Mark, Lauren and Amanda pull back the curtain and tell us about the various roles that go into putting it all together.

Two recent studies, from Shang et al. and Mejía-Ramírez et al., identify complementary mechanical mechanisms that regulate hematopoietic stem cell aging: external shear stress and internal nuclear envelope tension. These forces represent an evolutionary tradeoff between immediate immune defense and long-term stem cell maintenance.

Aging erodes the regenerative capacity of the gut, which weakens barrier function and repair. Eskiocak, Gewolb, Shah, Rouse, Chowdhury and colleagues show that senescent epithelial cells accumulate and drive this decline. Selective elimination of cells that express the senescence-associated surface marker uPAR using senolytic chimeric antigen receptor T cells restores stem cell function and rejuvenates the aged mouse gut.

We generated a mouse model of Alzheimer’s disease (AD) that replicates neuronal loss seen in patients, which overcomes a key barrier in the field. By reinstating the function of cyclin-dependent kinase 3 (CDK3), the model reliably exhibits human-like neurodegeneration, which opens a direct path towards evaluating CDK3 as a therapeutic target.

We developed scMORE (single-cell multiomics regulon enrichment), a computational framework that integrates single-cell multiomics with genome-wide association study summary statistics to identify transcription factor–chromatin–gene regulatory networks (eRegulons) that underlie complex diseases. Applying scMORE to 31 traits (including Parkinson’s disease), we investigated immune- and aging-associated eRegulons, and revealed how genetic variants shape cell-type-specific regulatory programs.

This Perspective proposes the Population Neuroscience-Dementia Syndemics Framework and model to develop knowledge of how multiple factors may interact to perpetuate inequities in dementia, especially for women in low- and middle-income countries.

The authors discuss the preclinical literature and emerging clinical evidence that support the rationale for investigating the use of glucagon-like peptide-1 receptor agonists to prevent and treat several neurodegenerative diseases of aging, with a focus on Alzheimer’s disease.

Mejía-Ramírez, Iáñez Picazo, Walter et al. explore how nuclear biomechanical changes limit the regenerative capacity of aged hematopoietic stem cells and show that targeting RhoA rejuvenates aged hematopoietic stem cells by reducing nuclear envelope tension and remodeling nuclear architecture.

Shang, Zhao, Ying and colleagues report that the mechanosensor PIEZO1 senses blood shear stress in hematopoietic stem cells, driving proliferation and myeloid bias. This axis links mechanical force to inflammation-induced aging, and PIEZO1 emerges as a potential therapeutic target.

uPAR is a senescence-associated protein, and CAR T cells targeting uPAR exert senolysis. Here Eskiocak et al. identify uPAR⁺ cells as key targets of intestinal aging and show that CAR T-mediated elimination prevents and restores age-related decline in intestinal regeneration and barrier function.

Jang and colleagues demonstrate that GDF3 reshapes the chromatin landscape of inflammatory adipose tissue macrophages and drives endotoxic inflammation with age. Pharmacological inhibition of the GDF3–SMAD2/3 axis alleviates endotoxemia lethality in old mice.

Liu et al. show that tumor-secreted dimethylarginine dimethylaminohydrolase-1 protein induces citrulline accumulation and promotes lung fibrosis and aging, shedding light on the cancer treatment and diagnosis by inhibiting senescent lung fibroblasts.

Wang, Xiao and colleagues develop and validate organ-specific proteomic aging clocks across large population cohorts in the UK, the USA and China, which show strong performance in tracking organ aging and predicting the risk of morbidity and mortality.

He, Wang, Shen, Dong and colleagues find that unsaturated fatty acids enriched in a black rice diet inhibit amyloid pathology, rescue cognition and restore physiological lifespan in mouse models of Alzheimer’s disease via allosteric activation of GPR120.

Zhuang, Zi et al. identify cyclin-dependent kinase 3 (CDK3) as a driver of neuron loss in Alzheimer’s disease that is associated with brain atrophy and memory decline in mice. Inhibition of CDK3 (BMX330) is shown to limit neuronal loss and improve cognition.

Kalia et al. investigate metabolic changes in Alzheimer’s disease (AD) using blood metabolomics, and show that lysophosphatidylcholines are associated with early amyloidosis in AD as measured by P-tau181 and P-tau217.

Delirium is a sudden change in mental function that is common in hospitalized older adults. To better understand this serious condition, Raptis et al. analyze large-scale genetic and proteomic datasets. They provide evidence that APOE-ε4 increases the risk for delirium independently of dementia, and highlight potentially clinically relevant plasma proteins.

The prostate is an important part of the male reproductive system whose aging process is incompletely understood. Sun et al. identify GRHL2 downregulation as a driver of prostate aging. They show that GRHL2 transactivates CDK19 to inhibit p53−p21 signaling and demonstrate that GRHL2 gene therapy alleviates age-related urinary dysfunction in mice.

In this technical report Ma et al. present scMORE, a polygenic method integrating single-cell multiomics and GWAS to prioritize cell-type-specific, trait-relevant eRegulons. scMORE revealed regulators underlying 31 immune and aging traits, including Parkinson’s disease.