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Uncovering a Conserved Pathway to Boost the Aging Heart and Extend Lifespan

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Review of “Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart” from Science Translational Medicine by Stuart P. Atkinson

The heart of an average 80-year-old will have beaten over 3 billion times, although current research suggests that there is minimal cell turnover or regeneration in the adult to aid repair and regeneration [1]. This suggested to the laboratories of Anthony Cammarato (Johns Hopkins University, Baltimore, USA) and Adam J. Engler (University of California, San Diego, USA) that an unknown molecular compensatory mechanism exists which can sustain the proper function of the heart over time. Their studies have concentrated on how aging may affect mechanotransduction, the signaling induced by changing physical forces.

Such forces are mediated through cytoskeletal proteins such as Vinculin, a protein overexpressed in aging patient myocardium [2] and mutated in some cases of heart failure [3]. In their exciting new study in Science Translational Medicine they have now shown that the Vinculin network has a central, conserved role in cardiac aging and, importantly, that cardiac-specific overexpression in Drosophila can enhance cardiac contractility and lifespan extension [4].  

An initial analysis of myocardia from aged rhesus monkeys (22 years) and rats (24 months) found a common pattern of protein expression, with abundant cytoskeletal proteins present in comparison to younger specimens. Of these proteins, the researchers chose to closely study Vinculin and proteins of the Vinculin interaction network in a more amenable model organism with a more rapid life cycle. 

In Drosophila, the researchers found that diastolic restriction, a hallmark of cardiac aging in Drosophila, correlated to the stiffening of the cortical actin cytoskeleton in cardiomyocytes and increases in the expression of cytoskeletal gene transcripts including Vinculin. However, this did not lead to contractile dysfunction, and instead correlated to the preservation of contractility. Additionally, myocardial specific over-expression of Vinculin in a fly strain without the age-related stiffening phenotype (w1118 flies) induced cardiac stiffness indicating a causative role for Vinculin in inducing age-related changes. These flies normally demonstrated a decline in heart function with age, but the overexpression of Vinculin mediated an improvement in cardiac contractility and an incredible 150% prolongation of lifespan in some flies.

This proof-of-concept study outlines a conserved mechanism which acts to “sure up” the aging heart via cytoskeletal remodeling resulting in improved contractility and lifespan extension. This is in contrast with previous studies which had surmised that cardiac cytoskeletal remodeling would result in stiffening and subsequent dysfunction [5], and this new finding will hopefully act as a platform for the creation of therapeutic interventions in aging patients. 

References

  1. van Berlo JH, Kanisicak O, Maillet M, et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014;509:337-341.
  2. Heling A, Zimmermann R, Kostin S, et al. Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium. Circulation research 2000;86:846-853.
  3. Vasile VC, Ommen SR, Edwards WD, et al. A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy. Biochemical and biophysical research communications 2006;345:998-1003.
  4. Kaushik G, Spenlehauer A, Sessions AO, et al. Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Science translational medicine 2015;7:292ra299.
  5. Perriard JC, Hirschy A, and Ehler E Dilated cardiomyopathy: a disease of the intercalated disc? Trends Cardiovasc Med 2003;13:30-38.