Abstract
Aging is the sum of the deleterious changes that occur as time goes by. It is the main risk factor for the development of cardiovascular disease, and aging of the vasculature is the event that most often impacts on the health of elderly people. The “free-radical theory of aging” was proposed to explain aging as a consequence of the accumulation of reactive oxygen species (ROS). However, recent findings contradict this theory, and it now seems that mechanisms mediating longevity act through induction of oxidative stress. In fact, calorie restriction − a powerful way of delaying aging − increases ROS accumulation due to stimulation of the basal metabolic rate; moreover, reports show that antioxidant therapy is detrimental to healthy aging. We also now know that genetic manipulation of the insulin-like-growth-factor-1/insulin signal (IIS) has a profound impact on the rate of aging and that the IIS is modulated by calorie restriction and physical exercise. The IIS regulates activation of nitric oxide synthase (eNOS), the activity of which is essential to improving lifespan through calorie restriction, as demonstrated by experiments on eNOS knockout mice. Indeed, eNOS has a key role in maintaining vascular integrity during aging by activating vasorelaxation and allowing migration and angiogenesis. In this review, we will overview current literature on these topics and we will try to convince the reader of the importance of vascular integrity and nitric oxide production in determining healthy aging.
Highlights
Max Rubner’s “rate of living” theory [1] combined massspecific resting metabolic rate and maximum lifespan of mammalian species to calculate the “lifetime energy potential”: it holds that the pace of life is inversely related to the length of life
With the introduction of a “lipids” perspective to the Free-radical theory of aging (FRTA), it was asserted that the level of peroxidizability of the cell membrane bilayer was a critical determinant of the severity of cell damage caused by free radicals: in response to attack by free radicals, peroxidation − the susceptibility to which is dictated by the number of single-bonded carbon atoms between the –C=C– units of the fatty acyl chain − generates a strong self-propagating reaction that causes damage to other molecules [5]
We recently reported that in children of nonagenarians the peroxidation index of erythrocyte membrane lipids was significantly lower than in a group of matched controls [9]
Summary
Max Rubner’s “rate of living” theory [1] combined massspecific resting metabolic rate and maximum lifespan of mammalian species to calculate the “lifetime energy potential”: it holds that the pace of life is inversely related to the length of life. In agreement with this hypothesis, deletion in worms of mitochondrial proteins such as ISP-1 and NUO-6 induces the oxidative stress necessary and sufficient for promoting longevity: this effect is abolished by antioxidants and is induced by mild treatment with oxidants [18] Taken together, these findings question Harman's FRTA and suggest, rather, that reactive oxygen species (ROS) act as essential signalling molecules promoting metabolic health and longevity through an eNOS/nitrate/trans fatty acids axis [19]. Administration of BH4 to older adults caused a selective improvement in endothelial vasorelaxation, demonstrating that BH4 potentially leads to eNOS recoupling in aged human vasculature [72] Another mechanism that reduces NO bioavailability, contributing to vascular endothelial dysfunction with aging, is oxidative stress [73]. A more recent clinical trial demonstrated acute reversal of endothelial dysfunction in elderly patients after oral administration of an antioxidant cocktail [87]
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