Akt2 Knockout Resists Cardiac Aging, Modestly Extends Life in Mice
Researchers here report on a life span study of mice genetically engineered to lack the Akt2 gene. The outcome is a greater resistance to the effects of aging on cardiac tissue, and a modest extension of life span. The researchers offer some thoughts on the likely mechanisms, suggesting that this is an example of the class of results that can be obtained via improved autophagy - though in this case, it is interesting that effects appear limited to cardiovascular tissues. The processes of autophagy act to remove damaged cellular components, particularly mitochondria, as well as many forms of metabolic waste. Thus I tend to read evidence for improved autophagy to slow aging as generally supportive of the SENS view of what should be done about aging, which is to say repair the molecular damage that causes aging. In principle the research community can build therapies that achieve a far greater and more effective level of repair than is possible through evolved mechanisms such as autophagy.
A number of hypotheses have been postulated for cardiac aging including oxidative stress, mitochondrial injury, autophagy dysregulation, and intracellular Ca2+ mishandling. Nonetheless, the precise machineries behind cardiac aging still remain somewhat elusive. Recent evidence from our laboratory and others has depicted a unique role for phosphoinositide 3-kinase (PI3K) and its downstream-signaling target protein kinase B (Akt) in aging-induced pathological changes in the heart. It was shown that the on-and-off switching of the PI3K/Akt pathway, particularly by insulin and insulin-like growth factor-1 (IGF-1), serves as a powerful physiological integrator rudimentary to life span and aging.
Our data have revealed an essential role for diminished autophagy, an evolutionarily conserved lysosome-dependent process for turnover of proteins and organelles, in Akt overactivation-induced accentuation of cardiac aging process. Autophagy plays a key role for biological aging process and cardiac homeostasis. Diminished autophagy has been shown to accelerate mammalian aging, in association with accumulation of damaged intracellular components including protein aggregate. Moreover, defective autophagy facilitates ventricular remodeling, contractile defects, and heart failure. Given the critical role for Akt in the regulation of cardiac survival and life span, this study was designed to examine the role of Akt2 ablation on aging-induced geometric, functional, and intracellular Ca2+ homeostatic changes in the heart, with a focus on autophagy and mitochondrial integrity.
Our findings indicated that Akt2 ablation prolongs life span and improves myocardial contractile function with a possible adaptive cardiac remodeling through the Sirt1-mediated autophagy regulation. In addition, Akt2 ablation alleviated aging-associated mitochondrial injury. Cardiac aging is characterized by unfavorable cardiac remodeling and function including cardiac hypertrophy, interstitial fibrosis, compromised contractility, and prolonged diastolic duration. To our surprise, Akt2 ablation negated aging-induced cardiac contractile dysfunction with a more pronounced remodeling. More prominent changes in heart mass/size, and cardiomyocyte cross-sectional area (but not fibrosis) were noted in aged Akt2-/- mice, favoring an important role for Akt2 in aging as opposed to young hearts. With the improved cardiac function in aging, the more pronounced cardiac hypertrophy in the face of Akt2 ablation seemed to suggest a state of adaptive cardiac hypertrophy in aged Akt2-/- hearts. Akt2 knockout did not elicit any notable cardiac effect at young age, suggesting that ablation of Akt2 may take time to impose cardiac remodeling and contractile effects.
Perhaps the most intriguing finding from our study is that Akt2 ablation prolonged life span and rescued against aging-induced cardiac dysfunction despite more pronounced cardiac hypertrophy. Several theories may be proposed for Akt2 ablation-elicited responses in aging. Earlier findings from our group depicted dampened phosphorylation of the Akt-negative regulator PTEN with aging, consistent with present observation of Akt activation in aging and the rationale of beneficial Akt2 ablation. Second, restored autophagy and mitophagy seem to play an important role for Akt2 ablation-induced cardioprotection. Both Akt activation, a key molecule governing cardiac survival, autophagy, and mitochondrial function, and aging have been shown to suppress autophagy. Our results revealed that Akt2 ablation restored autophagy and mitophagy in aging hearts. Our in vitro findings further revealed that autophagy induction with rapamycin improved mitophagy and contractile function. It is likely that restored autophagy and mitophagy may be responsible for prolonged survival in Akt2 knockout mice, in line with the prolonged life span with autophagy induction. Improved autophagy may improve diastolic function in senescent myocardium via preserved intracellular Ca2+ handling.
In summary, our findings suggest that Akt2 seems play an essential role in the regulation of longevity, cardiac geometry, and function in aging. Our data favor the notion that increased Akt signaling and downregulated Sirt1 with advanced aging may underscore reduced autophagy and mitophagy in aging, indicating the therapeutic potentials for Akt and autophagy/mitophagy in the management of cardiac aging. Although our study sheds some light on the interaction of Akt-Sirt1 signaling cascades on autophagy and cardiac homeostasis, the pathogenesis of cardiac dysfunction in aging, particularly in association with autophagy and mitochondria still deserves further investigation.
May be challenging to try to generalize findings regarding cardiac mitochondria and mitophagy from the heart to other organ systems because they operate quite different from any norm there. For example, one incredible finding last year, by none less then Dr. Wallce, of Doug wallace fame, is that in the crystallize cardiac arrays of mitochondria interposed between muscle units the mitos actually phase synchronize their cristae across the mito network. In other words they appear contionuous across the membrane separations between punctate mitos. https://www.nature.com/articles/ncomms7259
Embedded in this way one might suggest they would appear to have extra resistance to the normal akt2 regulated PTEN - Pink - Parking mitophagy paths because where theheck are the phagosomes and lysosomes even located here?
As far as 'the SENS vie of what should be done about aging' how would these isolated mitos even get allotopic nuclear genes in the first place and regulate them? For example, look what we know now about my allotopc CyB would be hopelessly suboptimal for normal people; Boom! - 'Assembly factors monitor sequential hemylation of cytochrome b to regulate mitochondrial translation'
http://jcb.rupress.org/content/205/4/511 Nicetry, but where would we be if we can't locally control how many electrons are confurcatedin the Q cycle at complex III? How it works here, basically, is that
'failure to hemylate cytochrome b sequesters the Cbp3-Cbp6 complex in early assembly intermediates, thereby causing a reduction in cytochrome b synthesis via a feedback loop that senses hemylation of cytochrome b.'
@johnhewitt
Thanks for the insights. Im also not sure the SENS strategy can cope with giant mitochondria which cannot be phagocytised. They accumulate in aging tissues and impair the mitophagy process.