DamAge / AdaptAge (causal damage clocks)

DamAge and AdaptAge are causality-aware epigenetic clocks developed by Kejun Ying and colleagues in the Gladyshev lab at Harvard / Brigham and Women's Hospital (Nature Aging, 2024). Not to be confused with stress-induced "damage clocks" such as the Sinclair lab's ICE-based constructs (Yang et al., Cell 2023), which describe induced epigenomic drift rather than causality-aware methylation clocks. Standard DNA-methylation clocks (Horvath, Hannum, GrimAge) are predictive but blind to whether CpG changes are causes or downstream consequences of aging. Using epigenome-wide Mendelian randomisation against longevity and disease GWAS, the authors identified CpGs causally linked to detrimental ageing outcomes (used to build DamAge - damaging methylation changes that accelerate biological age and correlate with mortality) and CpGs causally linked to beneficial outcomes (used to build AdaptAge - protective methylation changes reflecting compensatory adaptation). Both partition the broader CausAge signal by causal direction. They are responsive to short-term interventions and improve mechanistic interpretation of biological-age studies.