On being the right size: heart design, mitochondrial efficiency and lifespan potential

1. From the smallest shrew or bumble-bee bat to the largest blue whale, heart size varies by over seven orders of magnitude (from 12 mg to 600 kg). This study reviews the scaling relationships between heart design, cellular bioenergetics and mitochondrial efficiencies in mammals of different body sizes.\ud \ud 2. The [31P]-nuclear magnetic resonance-derived [phosphocreatine]/[ATP] ratio in hearts of smaller mammals is significantly higher (2.7 ± 0.3 for mouse; n = 22) than in larger mammals (1.6 ± 0.3 for humans; n = 13).\ud \ud 3. The inverse of the free myocardial cytosolic [ADP] concentration and the cytosolic phosphorylation ratio ([ATP]/[ADP][Pi]) scales with heart size and with absolute mitochondrial and myofibrillar volumes, close to a quarter-power (from −0.22 to −0.28; r = 0.99).\ud \ud 4. Assuming a similar mitochondrial P/O ratio and the same maximal amount of work required to convert 1 mol NADH to 0.5 mol O2 (i.e. 212.25 kJ/mol), the higher [ATP]/[ADP][Pi] ratios or cellular driving forces (ΔG'ATP) in hearts of smaller mammals imply greater mitochondrial efficiencies in coupling ATP production to electron transport as body size decreases. For a P/O ratio of 2.5, the mitochondrial efficiency in the heart of a shrew, mouse, human and whale is 84, 82, 71 and 65%, respectively.\ud \ud 5. Higher cytosolic ATP]/[ADP][Pi] ratios and ΔG'ATP values imply that the hearts of smaller mammals operate further from equilibrium than hearts of larger mammals.\ud \ud 6. As a consequence of scaling relationships, a number of remarkable invariants emerge when comparing heart function from the smallest shrew to the largest whale; the total volume of blood pumped by each heart in a lifetime is approximately 200 million L/kg heart and the total number of heart beats is approximately 1.1 billion per lifetime.\ud \ud 7. Similarly, the metabolic potential (total O2 consumed during adult lifespan per g bodyweight) for a 2 g shrew or a 100 000 kg blue whale is approximately 38 L O2 consumed or 8.5 mol ATP/g body mass per lifetime.\ud \ud 8. The importance of quarter-power scaling relationships linking structural, metabolic and bioenergetic design to the natural ageing process and maximum lifespan potential is discussed

The Effect of Long-term Dietary Supplementation with Antioxidantsa

The impact of diet and specific food groups on aging and age-associated degenerative diseases has been widely recognized in recent years. The modern concept of the free radical theory of aging takes as its basis a shift in the antioxidant/prooxidant balance that leads to increased oxidative stress, dysregulation of cellular function, and aging. In the context of this theory, antioxidants can influence the primary \u27intrinsic\u27 aging process as well as several secondary age-associated pathological processes. For the latter, several epidemiological and clinical studies have revealed potential roles for dietary antioxidants in the age-associated decline of immune function and the reduction of risk of morbidity and mortality from cancer and heart disease. We reported that long-term supplementation with vitamin E enhances immune function in aged animals and elderly subjects. We have also found that the beneficial effect of vitamin E in the reduction of risk of atherosclerosis is, in part, associated with molecular modulation of the interaction of immune and endothelial cells. Even though the effects of dietary antioxidants on aging have been mostly observed in relation to age-associated diseases, the effects cannot be totally separated from those related to the intrinsic aging process. For modulation of the aging process by antioxidants, earlier reports have indicated that antioxidant feeding increased the median life span of mice to some extent. To further delineate the effect of dietary antioxidants on aging and longevity, middle-aged (18 mo) C57BL\6NIA male mice were fed ad libitum semisynthetic AIN-76 diets supplemented with different antioxidants (vitamin E, glutathione, melatonin, and strawberry extract). We found that dietary antioxidants had no effect on the pathological outcome or on mean and maximum life span of the mice, which was observed despite the reduced level of lipid peroxidation products, 4-hydroxynonenol, in the liver of animals supplemented with vitamin E and strawberry extract (1.34 ± 0.4 and 1.6 ± 0.5 nmol/g, respectively) compared to animals fed the control diet (2.35 ± 1.4 nmol/g). However, vitamin E-supplemented mice had significantly lower lung viral levels following influenza infection, a viral challenge associated with oxidative stress. These and other observations indicate that, at present, the effects of dietary antioxidants are mainly demonstrated in connection with age-associated diseases in which oxidative stress appears to be intimately involved. Further studies are needed to determine the effect of antioxidant supplementation on longevity in the context of moderate caloric restriction