In the paper I'll point out today, researchers demonstrate one of the many ways in which insulin signaling and its surrounding mechanisms can be manipulated to slow specific measures of aging. In this case the focus is on the aging of heart tissue, and the methodology is genetic engineering to delete the gene encoding IGF-1R, the receptor for insulin-like growth factor 1 (IGF-1), a method already demonstrated to enhance longevity in mice.
A great deal of the aging research community restricts itself to cataloging the molecular biology of aging: firstly assessing which mechanisms are more or less important in the relationship between metabolism and aging, and secondly manipulating the operation of metabolism in order to produce new states with a modestly altered pace of aging. For most of these researchers therapies are not the goal, but rather only information. Where therapies do become the goal, the standard practice of developing drugs to alter metabolism so as to slow aging has so far demonstrated itself to be an expensive way to produce little but knowledge. Consider the hundreds of millions spent on sirtuin research, all the hype that accompanied that investment, and how little there is to show for it today. That is par of the course.
In the list of influential mechanisms linking cellular biochemistry with aging, insulin metabolism is perhaps the most studied and cataloged to date. It is of central importance in the behavior of cells, and as such this topic touches on numerous others: the role of growth hormone, diabetes, inflammation, regulation of cellular housekeeping activities, cellular senescence, and calorie restriction, as well as species life span and variations in aging, all areas of interest for diverse research groups in the life sciences. The researchers here deleted IGF-1R in heart tissue and observed the benefits in mice as they aged, looking for links to mechanisms known to be important in aging, such as inflammation and cellular senescence. The full text of this open access paper is only available in PDF format, I'm afraid, but here are some of the relevant portions:
The prevalence of cardiovascular disease increases with advancing age. In addition to long-term exposure to risk factors for heart disease, the aged heart exhibits intrinsic structural remodeling which reduces cardiac functional reserve and predisposes the heart to hemodynamic stress. Senescent remodeling includes left ventricular (LV) hypertrophy, diastolic dysfunction, interstitial fibrosis, and reduction in maximal heart rate.
Prior studies report that reduction of insulin/insulinlike growth factor (IGF)-1 signaling leads to longevity in a number of species. Notably, IGF-1R heterozygous knockout mice live on average 33% longer than their wild type controls without differences in food intake, physical activity or metabolic rate. However, it is not known if decreasing IGF-1R signaling in the heart can retard cardiac aging. We sought to test the hypothesis that long-term inactivation of IGF-1R in cardiomyocytes delays the development of aging-associated myocardial pathologies using very old cardiomyocyte-specific IGF-1R knockout mice.
The present study demonstrates that deletion of IGF-1R in cardiomyocytes attenuated aging-related cardiac pathologies, including ventricular hypertrophy, interstitial fibrosis, and inflammation. Mechanistically, we showed that IGF-IGF-1R-Akt signaling may be an essential regulator of cardiomyocyte senescence. IGF-1 is primarily produced in the liver following stimulation by growth hormone (GH) and acts by binding to IGF-1Rs to promote organ growth. The mRNA expression of GH in the pituitary declines with age in mice, as they do in humans. In parallel, serum IGF-1 levels decline progressively in healthy people from early adulthood to older age.
Our data provide novel evidence that physiological IGF-1R signaling promotes cardiomyocyte senescence and that long-term deletion of IGF-1R in cardiomyocytes prevents structural deterioration in aged hearts. It seems paradoxical that IGF-1R expression increased in aged hearts given that local IGF-1 or IGF-1R levels may decline with aging in mice. For example, in cerebral vasculature, expression of IGF-1 significantly decreases with age. Although the underlying mechanism is not understood, we speculate that induction of IGF-1R but not IGF-1 in aging hearts could represent a compensatory mechanism that promotes aging-associated cardiac remodeling. Thus, it could be anticipated that the very old IGF-1R knockout mice would display blunted cardiac hypertrophy under natural aging circumstances. Furthermore, aging related fibrosis was diminished in IGF-1R knockout mice hearts. The decreased fibrosis could be associated with an increased ability to adapt to hemodynamic stress. The capacity for adaptation to hemodynamic stress and ischemia is diminished in aged myocardium.
The heart produces proinflammatory cytokines such as TNF, IL-1, IL-6, and RANKL in pathological states, and these cytokines may promote cardiac remodeling by facilitating hypertrophy and fibrosis. Moreover, chronic inflammation is a characteristic of aging and senescent cells secrete components of the SASP, the senescence-associated secretory phenotype, including proinflammatory cytokines, chemokines, and proteases. Although the role of SASP in aging phenotypes has been extensively investigated, the association of cardiac inflammation with aging is not clearly defined. One of the salient features of our findings is that aging induces proinflammatory cytokines in the heart mediated by, at least in part, the IGF-1R system.