Abstract
Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of integrin-linked kinase (ilk) and β1-integrin (myospheroid, mys) in Drosophila, which colocalize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in Caenorhabditis elegans for ilk and in Drosophila for mys. Consistent with these findings, we observed elevated β1-integrin protein levels in old compared with young wild-type flies, and cardiac-specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin-linked kinase (ILK)/integrin pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK-associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that ilk/mys function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance and extend lifespan. Thus, ILK/integrin-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity.
Highlights
With age, heart function declines and the prevalence of heart disease is dramatically increased
We demonstrate that reduced integrin/integrin-linked kinase (ILK) ameliorates the effects of normal cardiac and organismal aging in Drosophila. ilk and mys heterozygotes live longer, but their hearts perform better at old age than wild-type controls, similar to young flies
Cardiac overexpression of mys causes a senescent-like phenotype in young flies. These findings suggest that the accumulation of b1-integrin at an older age may mediate in part the declining heart function and that a moderate reduction in integrin/ILK activity maintains youthful heart function with age
Summary
Heart function declines and the prevalence of heart disease is dramatically increased. The incidence of heart failure and atrial fibrillation is markedly increased in the elderly (Lakatta & Levy, 2003; Roger et al, 2011), which suggests that aging per se is a major risk factor for heart disease. Surgically exposed fly hearts show a regular myogenic beating pattern. As flies age, these heartbeats become less regular and show increased arrhythmias, which are reminiscent of the increased incidence of atrial fibrillation in elderly humans. Many fundamental aspects of cardiac aging seem to be conserved (Bodmer & Frasch, 2010; Dai et al, 2010), as is organismal aging (Kenyon, 2010)
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