Growth factors, nutrient signaling, and cardiovascular aging
Data from epidemiological data show an association between low serum IGF-I concentrations and increased cardiovascular mortality. In particular, a low serum IGF-I concentration is associated with coronary artery disease and diabetic vascular lesions. However, association is not equal to causation as indicated by recent data showing that several metabolic and hormonal factors play a crucial role in modulating the risk of developing chronic diseases and survival in mammals.
As discussed earlier, the down-regulation of IGF-I or similar signaling pathways by several dietary or genetic interventions has been shown to improve health and prolong lifespan in model organisms including mice. In agreement with these findings and in contrast to the epidemiological data described above, humans with mutations that cause constitutively very low levels of IGF-I do not display increased atherosclerosis but appear to be protected against diabetes and cancer (see following sections). Conversely, subjects with elevated GH/IGF-I due to acromegaly have a 2- to 3-fold increase in mortality due mostly to vascular disease but also to cancer and a variety of other diseases. The discrepancy between the above-mentioned studies on the effects of IGF-I on cardiovascular morbidity and mortality in humans may be due to confounding factors. Patients with coronary artery disease are exposed for many years to harmful cardiometabolic risk factors (i.e. type 2 diabetes, high blood pressure, dyslipidemia and most importantly chronic systemic inflammation).
Therefore, it is likely that inflammation (or other metabolic alterations), rather than low IGF-I, is responsible for the increased cardiovascular mortality in patients affected by CHD and that low IGF-I is another consequence of inflammation. In fact, the dramatic decline in serum IGF-I concentration induced by infections, trauma, and critical illness is not reversed by treatment with GH
Although the protection against both diabetes and cancer in GHRD subjects is in agreement with studies in mice, the normal longevity of GH and IGF-I deficient humans does not reflect the record mammalian life span extension observed in GH and IGF-I deficient rodents. One possible explanation for this disparity is the finding that many GHRD subjects die young of a variety of unusual causes. For example, 17% of the deaths in GHRDs were reported to be caused by convulsive disorders whereas 13% were alcohol-related, 20% were from accidents, and 17% from unknown causes representing a combined total of 67% of the deaths caused by these non-age-related causes, versus 34% unknown causes of death and 2% accidental deaths in the relatives. Whereas neither GHR nor GHRHR deficient subject appear to be long-lived, mutations that reduce the activity of the IGF-IR protein were overrepresented among centenarians, suggesting that lower activity but not severe deficiency in GH/IGF-I signaling may be more beneficial for longevity extension.
Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease