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Human genetics is a powerful tool for discovering causal mediators of human disease and physiology. Cardiovascular diseases with late onset in the lifecourse have historically not been considered genetic diseases, but in recent years the contribution of a heritable factor has been established. More importantly, over the last decade genome-wide association studies (GWASs) have identified many loci associated with late-onset cardiovascular diseases including coronary artery disease, carotid artery disease, ischemic stroke, aortic aneurysm, peripheral vascular disease, atrial fibrillation, valvular disease and correlates of vascular and myocardial function. Here we review findings from GWASs considered statistically robust with regard to multiple testing (p < 5 × 10 − 8 ) for late-onset cardiovascular diseases and traits. Although for only a handful of the 92 genetic loci described here have the mechanisms underlying disease association been established, new and previously unsuspected pathways have been implicated for several conditions. Examples include a role for NO signaling in myocardial repolarization and sudden cardiac death and a role for the protein sortilin in lipid metabolism and coronary artery disease. Genetic loci with multiple trait associations have also provided novel biological insights. For example, of the 46 genetic loci associated with coronary artery disease, only 16 are also associated with conventional risk factors for cardiovascular disease whereas the remaining two thirds may reflect novel pathways. Much work remains to functionally characterize genetic loci and for clinical utility, but accruing insights into the biological basis of cardiovascular aging in human populations promise to point to novel therapeutic and preventive strategies. This article is part of a Special Issue entitled ‘SI:CV Aging’. [ABSTRACT FROM AUTHOR]

“Inside every old person is a young person wondering what happened.” So, what is aging? Aging is a manifestation of progressive, time-dependent failure of molecular mechanisms that create disorder within a system of DNA and its environment (nuclear, cytosolic, tissue, organ, organism, other organisms, society, terra firma, atmosphere, universe). Continuous signaling, transmitted with different kinetics across each of these environments, confers a “mutual enslavement” that creates ordered functions among the components within the system. Accrual of this molecular disorder over time, i.e. during aging, causes progressive changes in the structure and function of the heart and arteries that are quite similar in humans, non-human primates, rabbits and rats that compromise cardiovascular reserve function, and confer a marked risk for incident cardiovascular disease. Nearly all aspects of signaling within the DNA environment system within the heart and arteries become disordered with advancing age: Signals change, as does sensing of the signals, transmission of signals and responses to signals, impaired cell renewal, changes in the proteome due to alterations in genomic transcription, mRNA translation, and proteostasis. The density of some molecules becomes reduced, and post-translational modifications, e.g. oxidation and nitration phosphorylation, lead to altered misfolding and disordered molecular interactions. The stoichiometry and kinetics of enzymatic and those reactions which underlie crucial cardiac and vascular cell functions and robust reserve mechanisms that remove damaged organelles and proteins deteriorate. The CV cells generate an inflammatory defense in an attempt to limit the molecular disorder. The resultant proinflammatory milieu is not executed by “professional” inflammatory cells (i.e. white blood cells), however, but by activation of renin–angiotensin–aldosterone endothelin signaling cascades that leads to endothelial and vascular smooth muscle and cardiac cells' phenotype shifts, resulting in production of inflammatory cytokines. Progressive molecular disorder within the heart and arteries over time leads to an excessive allostatic load on the CV system, that results in an increase and “overshoot” in the inflammatory defense signaling. This age-associated molecular disorder-induced inflammation that accrues in the heart and arteries does not, itself, cause clinical signs or symptoms of CVD. Clinical signs and symptoms of these CVDs begin to emerge, however, when the age-associated inflammation in the heart and arteries exceeds a threshold. Thus, an emerging school of thought is that accelerated age-associated alterations within the heart and arteries, per se, ought to be considered to be a type of CVD, because the molecular disorder and the inflammatory milieu it creates within the heart and arteries with advancing age are the roots of the pathophysiology of most cardiovascular diseases, e.g. athersclerosis and hypertension. Because many effects of aging on the CV system can be delayed or attenuated by changes in lifestyle, e.g. diet and exercise, or by presently available drugs, e.g. those that suppress Ang II signaling, CV aging is a promising frontier in preventive cardiology that is not only ripe for, but also in dire need of attention! There is an urgency to incorporate the concept of cardiovascular aging as a disease into clinical medicine. But, sadly, the reality of the age-associated molecular disorder within the heart and ateries has, for the most part, been kept outside of mainstream clinical medicine. This article is part of a Special Issue entitled CV Aging. [ABSTRACT FROM AUTHOR]

DNA and histone methylation are well characterized epigenetic marks that are altered during the aging process. In aged cells and tissues, DNA cytosine tagging by methylation undergoes the so-called “epigenetic drift”, in parallel with a change in the methylated histone profile. Despite the large body of knowledge regarding age-dependent epigenetic changes, there are few reports related to this topic in the cardiovascular field. This review summarizes age-dependent changes in DNA and histone methylation with a specific focus on age-related cardiovascular diseases (CVDs). [ABSTRACT FROM AUTHOR]