rs115741257 (RPSAP72-TENT5A): Aging Decline

Key takeaways

• rs115741257 was identified in a 2025 genome-wide association study of longitudinal cognitive and physical aging in the UK Biobank, distinguishing genetic effects on baseline ability from effects on rate of decline
• Baseline physical function shows markedly higher heritability (about 31%) than the rate of physical decline (about 3%), suggesting distinct genetic mechanisms govern each
• Cognitive decline in the study was primarily attributable to Alzheimer's disease genetic liability, while physical decline was primarily tied to telomere length and bone mineral density
• Genetic loci associated with the speed of aging decline appear largely non-overlapping with those associated with where a person starts

What the research says

rs115741257, in the RPSAP72 - TENT5A genomic region, was examined in a UK Biobank genome-wide association study (GWAS, a large scan across the full genome to find variants linked to a trait) of longitudinal aging phenotypes by Schoeler, Pingault, and Kutalik, published in Nature Communications in 2025. That study found that baseline function and accelerated decline have distinct genetic architectures: baseline physical function showed 31.38% heritability (the share of variation across individuals attributable to genetic differences) versus just 3.15% for the rate of physical decline, and different sets of loci were linked to each outcome. At the pathway level, cognitive decline was primarily attributed to Alzheimer's disease polygenic liability (Mendelian Randomization standardized effect = 0.17, where Mendelian Randomization is a causal inference technique that uses genetic variants to estimate cause-and-effect relationships), while physical decline was primarily linked to telomere length (effect = -0.05) and bone mineral density (effect = -0.05).

Reported associations

• Longitudinal aging trajectories: This variant appears as a locus in a GWAS of longitudinally measured cognitive and physical aging outcomes in the UK Biobank; specific per-allele effect sizes and statistical significance for this individual variant are not detailed in the available study excerpt
• Cognitive aging: The study identified Alzheimer's disease genetic liability as a primary pathway for cognitive decline, with broader GWAS discovery of loci across this domain
• Physical aging: Physical decline was associated with telomere-length and bone-mineral-density pathways, with the specific locus DUSP6 linked to physical decline trajectories in the same study

Evidence quality

This variant was identified within the UK Biobank, a large prospective cohort. The GWAS used simulation-validated two-wave longitudinal models, addressing methodological limitations of cross-sectional aging research. Schoeler and colleagues explicitly flag selective attrition and participation bias as important caveats: individuals with two waves of data represent a healthier subset of an already health-selected sample, which may limit generalizability. Specific discovery statistics for this variant (p-value, confidence interval, and effect size) are not reproduced in the study excerpt available here, and independent replication of this variant's association has not been reported in the available materials. The pathway-level findings (Alzheimer's disease liability for cognitive decline; telomere length and bone mineral density for physical decline) are derived from Mendelian Randomization rather than direct single-variant association, with modest standardized effects (0.17 and -0.05, respectively), and should be considered preliminary pending replication.

Lifestyle considerations

No lifestyle considerations on file for this variant.