This very readable open access paper discusses some of the mechanisms involved in cardiovascular aging. As for many such publications, and to my eyes at least, it leans too much towards the details of the aged metabolism rather than towards the underlying causes that make the cells of an aged cardiovascular system behave differently. Near all medicine for age-related disease has so far focused on trying to change the way in which cells behave in response to the causes of aging, without addressing those causes, and, as a result, beneficial outcomes have been marginal at best. It is somewhere between very hard and impossible to make a damaged machine run well without actually repairing the damage. The approach we take to aging, cardiovascular or otherwise, should be one of periodic repair of root causes.

All around the world, scientists are trying to beat age-related diseases, such as heart attacks, cancer, and dementia; stop people getting ill is an obvious goal to aid the individual wellbeing and reduce pressure on society. At the whole organism level, aging has been defined as the time-related deterioration of the physiological functions necessary for survival and fertility. This definition applies to all the individuals of a species and overlaps with disease-related aging. Aging of the vasculature plays a key role in morbidity and mortality of older people. It is often assimilated with endothelial dysfunction, that is, the failure of vascular endothelial cells to respond to vasoactive stimuli and mount reparative transformation upon tissue damage. Zooming into the molecular level, aging of the vasculature consists in small, incremental amounts of damage that spreads to all vascular cells, including vascular smooth muscle cells and pericytes, and, owing to the system dependency on vascular homeostasis, to tissues and organs; eventually, the whole organism will suffer from this accumulation of damage.

The development of novel treatments targeting vascular aging and prevention of age-related vascular pathologies requires a better knowledge of the cellular and functional changes that occur in the vasculature during aging. These include oxidative stress, mitochondrial dysfunction, susceptibility to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, and stem cell dysfunction. Senescent cells secrete autocrine or paracrine factors, including cytokines, growth factors, proteases, and soluble receptors called senescence-associated secretory phenotype (SASP).

The capacity to repair and regenerate empowers living organisms with resilience to natural fluctuations and events that cause disturbance or damage. Aging and regeneration are two sides of the same coin and this has been confirmed through the examination of species with extreme regenerative capabilities, such as planarians and salamanders, which show no signs of aging or quantifiable age-associated functional decline. In contrast, in complex organisms like humans, aging is characterized by a decay in the regenerative capacity and reparative activities. Tissue-specific stem cells and progenitor cells incur in age-related defects, such as the loss of self-renewal capacities and proliferative activity and the deterioration in functionality and potency. Likewise, differentiated cells become progressively uncapable of regulating protein synthesis and metabolism, especially under stress conditions, eventually undergoing irreversible proteotoxic damage. Exhaustion of compensatory mechanisms increases the susceptibility to risk factors and diseases and results in excess morbidity and mortality.

Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.