Cardiac aging can be regarded as a progressive decline in heart function that is intrinsic to the organ itself and that correlates with the age of the organism. Most elderly adults are much more concerned about preserving their functionality later in life rather than simply extending their lifespan (Phelan et al. 2004
). For this reason the study of functional senescence of the heart as distinguished from its effect on global mortality becomes important. Some genes that specifically influence the functional status of the organ may not affect organismal survival. It will be interesting to distinguish between those processes that regulate lifespan from those that control age-dependent decline in individual organ systems.
One of the most notable phenotypes of cardiac senescence in humans and rodents is the reduction in maximum heart rate that can be achieved under stress (Lakatta 2001
). This phenomenon of impaired cardiovascular acceleration during stress is a biomarker of mammalian cardiac aging, but its genetic basis is not well-determined, partly owing to the complex interactions between genes, age, disease and lifestyle (Lakatta 2001
). An initial understanding of the interactions may only be possible by examining cardiac aging using simpler genetic animal models.
In this regard, Drosophila
may be uniquely situated for studies of cardiac aging, since it is the only one among other simple genetic models that possesses a fluid pumping heart (Bier and Bodmer 2004
). Because the survival of the organism is not as tightly coupled to heart function as it is in vertebrates it will be possible to investigate this organ’s senescence in relative independence of organismal senescence. Moreover, the maximal heart rate of Drosophila
under stress conditions, such as elevated ambient temperature and external electrical pacing, is also significantly and reproducibly reduced with aging, analogous to observations in elderly humans (Paternostro et al. 2001
, Wessells et al. 2004
). Thus, Drosophila
with its versatile genetic tools can also be exploited for identifying and studying genes involved in cardiac functional senescence. Again, the insights from these studies are likely to significantly impact the field of human cardiac pathology and aging.
Several genes and pathways have already been identified that play a crucial role in fly cardiac aging. The Drosophila SUR
) encodes a subunit of the ATP- sensitive potassium channel (KATP
). which plays important roles in various cellular processes by coupling cell metabolism to electrical activity (Akasaka et al. 2006
, Seino 1999
). The expression of dSUR
in the heart is dramatically diminished in the aging heart, and RNAi-mediated knockdown of dSUR
in young fly hearts phenocopies aged hearts under conditions of pacing-induced stress (Akasaka et al. 2006
). These results provide evidence for a role of dSUR in protecting against declining performance during cardiac aging. Mutations in human SUR2, the mammalian homolog of dSUR, result in cardiomyopathy by compromising K ATP channel function (Bienengraeber et al. 2004
), and it is possible that a reduction in K ATP
channel activity could cause membrane electrical instability, especially in older hearts (Akasaka et al. 2006
). This suggests that similar to the fly’s dSUR, human SUR2 may also protect against cardiac senescence.
The insulin/insulin-like growth factor (IGF) signaling is a well-established genetic pathway that regulates longevity (Kenyon 2001
, Tatar et al. 2003
mutants of insulin-like receptor
) and chico
(encoding the insulin receptor substrate) extend the lifespan of the organism (Clancy et al. 2001
, Tatar et al. 2001
) as well as protect their hearts from two age-related phenomena: decreases in resting heart rate and increases in heart failure resulting from pacing-induced stress (Wessells et al. 2004
). Additionally, interfering with InR signaling exclusively in the heart, by overexpressing the phosphatase dPTEN (a negative regulator of insulin/IGF signaling) or the forkhead transcription factor dFOXO (a negatively-regulated target of insulin/IGF signaling), prevents the decline in cardiac fitness with age (Wessells et al. 2004
). These data indicate that insulin-like signaling is involved in both systemic as well as cardiac -specific senescence. Moreover, the ablation of insulin-producing cells (IPCs) in flies also slows demographic aging and reduces age-dependent heart failure (Wessells et al. 2004
), indicating that both a reduction of insulin receptor signaling and circulating insulin levels influence organismal aging and age-related cardiac susceptibility to pacing stress. This is consistent with the observations that overexpressing dFOXO in the adult fat body results in long-lived flies (Giannakou et al. 2004
, Hwangbo et al. 2004
), whereas cardiac-specific overexpression of InR and dPTEN do not seem to affect the overall lifespan of the animal (Wessells, et al., 2004
). Lifespan-altering manipulation of insulin/IGF signaling specifically in the fat body of the head also decreases insulin production from the IPCs, thus affecting longevity and possibly organ senescence indirectly, which is suggestive of a complex coordination of aging with organ-autonomous endpoint effects (Hwangbo et al. 2004
, Wessells et al. 2004
Interestingly, upregulating the expression level of dFOXO in the adult fat body protects against the oxidative stressor paraquat (Hwangbo et al. 2004
), raising the possibility that insulin-like signaling could, at least in part, delay cardiac performance senescence via reducing oxidative stress damage. However, in the chico
mutants with extended lifespan (Clancy et al., 2001
) and lowered cardiac aging (Wessells et al. 2004
), there seems to be no alteration in their resistance to oxidative stress (Clancy et al. 2001
). Thus, the contribution of oxidative damage to heart functional aging remains to be further examined.
Another example of how alteration in energy homeostasis could be coupled to aging and organ senescence is illustrated by manipulations of the Drosophila
Target of Rapamycin (dTOR) pathway. In addition to its well-studied role in nutrient sensing and cellular growth in response to insulin/IGF and PI3K, TOR signaling is also involved in global lifespan regulation in model organisms. A recent study further showed that lowering TOR activity in Drosophila
prevents age-dependent functional decline of heart performance, and this could be attributed to a reallocation of energy stores preferentially for the regulation of “long term” responses such as lifespan and organ maintenance (Luong et al., 2006
). Collectively, these findings support the notion that insulin/TOR signaling plays an important role in modulating organismal and cardiac aging, and it remains to be determined whether TOR regulates cardiac functional senescence via its known downstream effectors such as S6K and 4E-BP, or through some other novel factors. Given the high degree of parallel mechanisms controlling organismal aging and lifespan, it is likely that the mechanisms underlying cardiac functional aging in flies are also conserved, and will have significant implications on mammalian heart aging and physiology.