Sex-specific aging clocks from a large-scale human phenome reveal distinct aging transitions and circulating signatures.

Sex-specific clinical aging clocks revealed divergent aging trajectories between women and men during midlife that converged in later life.

• Clocks were built from 172 clinical measures across more than 100,000 participants aged 18-98 years.
• The study used a cross-sectional design across three centers under the Multicentric Chinese Aging Study (mCAS).
• Divergence in aging trajectories was observed specifically during midlife, with convergence occurring in later life.
• Separate clocks were constructed for each sex to capture these distinct aging patterns.

Age-related accumulation of metabolic factors including low-density lipoprotein (LDL), triglycerides, glucose, and uric acid was identified through phenome-wide analyses.

• These factors were identified as age-accumulating through phenome-wide analyses of 172 clinical measures.
• The accumulation of these metabolic factors was observed across the lifespan in the large cross-sectional cohort.
• These findings implicate metabolic burden as a driver of biological aging in humans.
• The study characterized these as 'actionable drivers of human aging.'

Tumor markers carcinoembryonic antigen (CEA) and human epithelial protein 4 (HE4) showed age-related accumulation in the general population.

• Both CEA and HE4 were identified as age-accumulating factors in phenome-wide analyses.
• These markers, typically used in cancer screening, were found to increase with age in the general population.
• Their age-related accumulation was captured alongside metabolic factors in the same phenome-wide framework.
• The study categorizes these tumor markers alongside metabolic factors as actionable aging drivers.

Age-accumulating metabolic factors induced senescence-related phenotypes in human endothelial cells.

• The identified age-accumulating circulating factors were tested experimentally in human endothelial cells.
• Treatment with these factors resulted in senescence-related phenotypes, providing a mechanistic link between circulating metabolic burden and cellular aging.
• This finding supports a causal or contributory role of these factors in driving aging biology.
• The experiments were conducted in vitro using human endothelial cells as the model system.

A high-fat diet mouse model with dietary reversal supported the modifiability of metabolic burden-induced aging.

• Mice were subjected to a high-fat diet to induce metabolic burden, and then dietary reversal was applied.
• The dietary reversal experiment demonstrated that metabolic burden-induced aging signatures could be modified.
• This in vivo model provides evidence that interventions targeting metabolic factors may be able to slow or reverse aging-related changes.
• The finding supports the concept of 'actionable' aging drivers that are responsive to lifestyle or dietary interventions.

The study profiled 172 clinical measures from more than 100,000 participants aged 18-98 years across three centers in China.

• This is described as a large-scale cross-sectional analysis under the X-Age Project.
• Participants were drawn from the Multicentric Chinese Aging Study (mCAS).
• The age range of 18-98 years enabled characterization of aging trajectories across the full adult lifespan.
• Three centers contributed to the multicentric design, supporting generalizability within the studied population.

The study established metabolic and tumor marker accumulation as actionable drivers of human aging, supporting personalized, sex-stratified geroprotective interventions.

• Sex-specific aging clocks enabled the identification of sex-stratified aging patterns and biomarkers.
• The convergence of male and female aging trajectories in later life was a key finding informing the sex-stratified approach.
• The authors propose that these findings 'pave the way for personalized, sex-stratified geroprotective interventions.'
• The combination of clinical phenomics, cellular experiments, and animal models was used to support the actionability of identified aging drivers.