Ferrucci et al Time and the Metrics of Aging 741 disease, and all-cause mortality, although the causal nature of these associations and whether telomere shortening affects the aging process have been questioned. 4, 5 Predictable changes in DNA methylation—a fundamental epigenetic mechanism—track chronological age in humans, as well as phenotypic changes that occur during the lifespan and predict risk of incident coronary artery disease and cardiovascular mortality, as well as a wide range of adverse outcomes. 6, 7 Why this specific methylation pattern emerges with aging and how it relates to pathology remains unknown. Genetic animal models have revealed that defects in autophagy or mitophagy cause cardiovascular disorders, including cardiac myopathy and heart failure. 8 Evidence of defective autophagy is present in cardiac myocytes isolated from humans with ischemic heart disease and heart failure, but whether autophagy is an epiphenomenon or a causative factor is unclear. Autophagy flux has been assessed recently using human lymphocytes, demonstrating that activation-induced autophagy is preserved in CD4+(cluster of differentiation 4) T cells in individuals from families with exceptional longevity compared with age-matched controls. These effects are also associated with higher T-cell functioning. 9 The age-related decline in mitochondrial oxidative capacity is associated with insulin resistance, decreased muscle strength, and diminished walking performance, with some evidence of a causal association. 10, 11 However, there is little longitudinal data that connects age-related changes in mitochondrial dysfunction with phenotypic and pathological changes in aging.

Senescent cells accumulate with aging in multiple tissues. 12 Studies from animal models suggest that senescence traits contribute to the whole atherosclerosis process, from senescent foamy macrophages accumulating in the subendothelial space, to the production of atherogenic and inflammatory cytokines, to the appearance of senescent vascular smooth muscle cells that promote plaque instability.