The authors of this paper argue that stochastic mutational damage to nuclear DNA is important in the progression of vascular aging, the declining function and structural integrity of blood vessels. It is more or less the consensus hypothesis that nuclear DNA damage does broadly contribute to all facets of the aging process by causing a growing random dysregulation of cellular activity, and is not just a matter of cancer risk. There those who argue the opposite position, however, that while this is damage, outside of cancer risk nuclear DNA mutations don't create enough disarray over a normal human lifetime to matter in comparison to other forms of cell and tissue damage. As for most of the molecular damage of aging, there is a lot of room to argue over relative importance because there are few presently available ways to repair any one form of damage in isolation to see what happens. If all forms of damage could be so repaired, then the research community would certainly know how important each was, but that still lies in the future.
Cardiovascular diseases (CVD) are the leading cause of death worldwide, responsible for killing 17.3 million persons per year. The onset of CVD is triggered by vascular endothelial alterations characterized by an impaired endothelium-dependent vasodilation, the overproduction of pro-inflammatory and prothrombotic molecules, and oxidative stress. Age is the strongest independent predictor for CVD in risk scores in middle-aged persons, and an important determinant for cardiovascular health in the population aged 65 or older. Aging is characterized by the complex interaction of cellular and molecular mechanisms that leads to a collection of functional problems. Focusing on the vasculature, such problems are closely associated with each other, and include worsened vasodilation, increased arterial stiffness and overt remodeling of the extracellular matrix, diffuse intimal thickening and a dysfunctional endothelium. The mechanisms through which age actually contributes to cardiovascular risk remain the subject of speculation.
A recently proposed alternative view on vascular aging has emerged that presents new mechanistic alternatives for understanding the process of vascular aging. In this novel paradigm, causal mechanisms for the process of aging itself, most notably genomic instability, including telomere attrition, drive the detrimental changes occurring increasingly with (biological) aging. In the present review we summarize the evidence that supports the role of genomic instability in vascular aging. In addition, we present mechanisms through which genomic instability generates the functional changes that are typical for the aging vasculature.
Nuclear DNA lesions, among which is telomere erosion, and mitochondrial DNA damage are strongly associated with several main features of vascular aging, such as diminished vasodilator capacity and increased vasoconstriction, increased blood pressure, increased vascular stiffness and atherosclerosis. Pivotal cellular biological changes involved in these pathological features comprise cellular senescence, apoptosis, autophagy, stem cell exhaustion and altered proliferative capacity of vascular cells. The role of gene mutation and of compromised transcription remains unknown. Potential mediating signaling pathways involved include components of the survival response, notably antioxidants under regulation of Nrf2 (beneficial), increased inflammatory status (detrimental) and decreased IGF-1/GH signaling (detrimental), as well as the interplay between mTOR, AMPK and NFκB, SIRT-1, and PAI-1, p53- and p21- and p16-related signaling. Proposed remedies against genomic instability-related vascular aging include PAI-1 inhibition, mTOR inhibition, dietary restriction, senolytics, PDE1 and PDE5 inhibitors and stimulators of Nrf2.