Ageing

Energetics and Ageing

Our work on ageing falls into two related topics.

  1. Testing the ‘rate of living – oxidative stress’ hypothesis
  2. Exploring the effect of caloric restriction on energy demands and lifespan.

Testing the ‘rate of living oxidative stress’ hypothesis.

The idea that organisms are a like machines that wear out and ultimately malfunction (die) with continued use probably arose in the industrial revolution. It was the German scientist Max Rubner (1908) however who made the first linkage between metabolic rate as a measure of how much work an animals does and how long it lives. By comparing across a small range of species Rubner showed that larger animals have much lower metabolic rates per gram of tissue than small animals and they also live longer. This led ultimately to the ‘rate of living’ theory by Raymond Pearl, published as a book in 1928. The idea that energy metabolism is linked to lifespan gained a significant boost in the 1950s with the emergence of the idea that energy metabolism generates free-radicals which cause damage to macromolecules. This provided a direct mechanistic link between energy metabolism and ageing. Our work has been focussed on testing these ideas. In particular we have been interested in whether these effects are replicated when one looks within species rather than between species. We have performed several experimental manipulations of animals to test the predictions of the ‘rate of living – free-radical damage’ hypothesis including experimentally increasing animal energy demands over the lifespan and feeding animals antioxidants to quench free-radical production.

The main findings from our work are:

  1. Within species it appears to be the animals with greater metabolic rates that live longer, not those with lower expenditure. This may be related to the role of uncoupling proteins in mitochondria that quench free-radical production at the same time as elevating metabolic rate.
  2. Experimental manipulation of energy expenditure (increasing it by c 50% over the lifespan) does not shorten lifespan – in the absence of any compensatory effects in free-radical scavenging and repair.
  3. Supplementing the diet with vitamin C has no effect on lifespan but supplementing with vitamin E does. The absence of an effect of vitamin C is because any antioxidant effect if offset by a reduction in endogenous protection. This positive effect of vitamin E appears to be related however to the anticancer properties of vitamin E rather than being mediated via its antioxidant effects.

Publications in this area

pdfs for most of the following publications in this and the other sections are available for  free download here

  • Selman, C., McLaren, J.S., Collins, A.R., Duthie, G.G. and SPEAKMAN, J.R. (2008)
    The impact of experimentally elevated energy expenditure on oxidative stress and lifespan in the short-tailed field vole Microtus agrestis.
    Proceedings of the Royal Society of London B 275:1907-16.
    This paper was subject of an ‘outside JEB’ article in the Journal of Experimental Biology in November 2008. ‘Voles live fast but don’t die young’ by Darveaux, C. (JEB 211: issue 21 v-v).
  • Furness, L. and SPEAKMAN, J.R. (2008)
    Energetics and longevity in birds.
    AGE 30: 75-87
  • Haggerty, C., Hoggard,N., Brown,D.S., Clapham, J.C. and SPEAKMAN, J.R. (2008)
    Intra-specific variation in resting metabolic rate in MF1 mice is not associated with membrane lipid desaturation in the liver
    Mechanisms of Ageing and Development 129: 129-137
  • Selman, C., Lingard, S, Choudhury, A.I., Batterham, R.L., Claret, M., Clements, M., Ramadani, F., Okkenhaug, K., Schuster, K., Blanc, E., Piper, M.D., Al-Qassab, H., SPEAKMAN, J.R., Carmignac, D., Robinson, I.C.A., Thornton, J.M., Gems, D., Partridge, L. and Withers, D.J. (2008)
    Extended lifespan with reduced age-related pathology in insulin receptor substrate 1 null mice
    FASEB J. 22: 807-818
  • Selman, C., McLaren, J.S., Mayer, C., Duncan, J.S., Collins, A.R., Duthie, G.G., Redman, P.,
    and SPEAKMAN, J.R. (2008)
    Lifelong α-tocopherol supplementation increases median lifespan of C57BL/6 mice in
    the cold but has only minor effects on oxidative damage.
    Rejuvenation Research 11: 83-95.
  • Vaanholt, L.M., SPEAKMAN, J.R., Garland T., Lobley, G.E., and Visser, G.H. (2008)
    Protein synthesis and antioxidant capacity in ageing mice: effects of long-term voluntary exercise.
    Physiological and Biochemical Zoology 81: 148-157.
  • Selman, C., McLaren, J.S., Meyer, C., Duncan, J.S., Redman, P., Collins, A.R., Duthie, G.G.
    and SPEAKMAN, J.R. (2006)
    Life-long vitamin C supplementation in combination with cold exposure does not
    Affect oxidative damage or lifespan in mice, but decreases expression of antioxidant protection genes
    Mechanisms of Ageing and Development 127: 897-904
  • Judge S, Jang YM, Smith A, Selman C, Phillips T, SPEAKMAN, J.R., Hagen T,
    Leeuwenburgh C. (2005)
    Exercise by lifelong voluntary wheel running reduces subsarcolemmal and interfibrillar mitochondrial hydrogen peroxide production in the heart.
    American Journal of Physiology 289: R1564-1572.
  • SPEAKMAN, J.R. (2005)
    Correlations between physiology and lifespan – two widely ignored problems with
    comparative studies.
    Aging Cell 4: 167-175
  • SPEAKMAN, J.R. (2005)
    Body size, energy metabolism and lifespan
    Journal of Experimental Biology 208: 1717-1730
    By November 2007 this paper was the 5th highest cited paper that had been published during 2005 by JEB, from a total of 599 articles published that year.
  • Yearsley, J.M., Kyriazakis, I., Gordon, I.J., Illius, A.W., Johnston, S.L., SPEAKMAN,
    J.R. and Tolkamp, B.J. (2005)
    A life history model of somatic damage associated with resource acquisition: damage protection or prevention?
    Journal of Theoretical Biology 235: 305-317
  •  SPEAKMAN, J.R., Talbot, D.A., Selman, C., Snart, S., McLaren, J.S., Redman, P., Krol,
    E.Jackson, D.M., Johnson,M.S. & Brand, M.D. (2004)
    Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial
    uncoupling and live longer.
    Aging Cell 3:87-95
    This paper was featured on the front of the journal. It was widely reported in the popular media.
  • Wiersma, P., Selman, C., SPEAKMAN, J.R. and Verhulst, S. (2004)
    Birds sacrifice oxidative protection for reproduction
    Proceedings of the Royal Society Series B 271: 360-365S
  • SPEAKMAN, J.R., van Acker, A., and Harper, E.J. (2003)
    Age related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy.
    Aging Cell.2: 265-279
    (see independent review of this paper in Science 12th Sept 2003)
  • SPEAKMAN, J.R. (2003)
    Oxidative phosphorylation, mitochondrial proton cycling, free-radical production and aging. Pp 35-68 In Mattson, M.P. (ed). Energy metabolism and lifespan determination. Elsevier series Advancesin Cell Aging and Gerontology.Elsevier Amsterdam
  • Selman, C., Grune, T., Stolzing, A., Jakstadt, M., McLaren, J.S, & SPEAKMAN, J.R.
    (2002)
    The consequences of acute cold exposure on protein oxidation and proteasome activity in short-tailed field voles, Microtus agrestis
    Free Radical Biology and Medicine 33: 259-265.
  • Selman, C., McLaren, J.S., A.R. Collins, G.G. Duthie and SPEAKMAN, J.R. (2002)
    Anti-oxidant enzyme activities, lipid peroxidation and DNA oxidative damage: the effects of short-term voluntary wheel running.
    Archives of Biochemisty and Biophysics 401: 255-261
  • SPEAKMAN, J.R., Selman, C., McLaren, J.S. and Harper, J.E. (2002)
    Living fast, dying when? The links between energetics and ageing.
    Journal of Nutrition132: 1583-1597S.
  • Jackson, D.M., Trayhurn, P. and SPEAKMAN, J.R. (2001)
    Associations between energetics and over-winter survival in the short-tailed field vole Microtus agrestis.
    Journal of Animal Ecology 70: 633-640.
  • Selman, C., McLaren, J.S., Himanka, M.J. and SPEAKMAN, J.R. (2000)
    Effects of long-term cold exposure on antioxidant enzyme activities in a small mammal.
    Free Radical Biology and Medicine 28 Iss 8: 1279-1285.
  • Cleaver, J.E., SPEAKMAN, J.R. and Volpe, J.P.G. (1995)
    Nucleotide excision repair: Variations associated with cancer development and speciation.
    Cancer Surveys 25: 125-142.

Caloric restriction

Caloric restriction is the only non-genetic manipulation of animals that reliably increases lifespan via an effect on the rate of ageing. The effects of CR are so convincing in animal studies that already some people have started to voluntarily restrict their intake in the hope that they too will increase their lifespans. 

Several organisations promoting the CR lifestyle have already been formed.

The calore restriction society

The Cronies  (Calorie restriction with Optimal nutrition)

Roy Walford's calorie restriction site. Walford was one of the researchers that went in the Biosphere 2 project in Ariziona where he spent 2 years in involuntary restriction. He emerged and continued restricting his intake and wrote several books on the power of CR to increase lifespan.

In addition to these volunteer organisations the NIA in the US have also sponsored a randomised clinical trial to evaluate the effectiveness of CR in humans. The trial is called CALERIE (Comprehensive Assessment of the Long-term Effects of reduced Intake of Energy). The CALERIE study is run across three sites, the Pennington Biomedical Research center in Baton-Rouge (PI: Eric Ravussin), The Jean-Meyer Nutrition research center at Tufts in Boston (PI Susan Roberts), 

and the School of Medicine at the Washington  University in St louis (PI John Holloszy). The study is cordinated from Duke University. The coordinating centre site can be accessed here.

The impact of CR on energy metabolism has been controversial for at least 25 years. Our work has been exploring the mechanism of action of CR addressing two quite separate aspects. First what are the energetic consequences of CR and second how is the somatic protection programme switched on – in particular the role of hunger neuropeptides in the brain. This latter question is the subject of a large current BBSRC research grant.

for more details see "The Systems Biology of Caloric Restriction"

Publications in this area

  • Hambly, C., Mercer, J.G. and SPEAKMAN, J.R. (2007)
    Hunger does not diminish over time in mice under protracted caloric restriction.
    Rejuvenation Research 10: 533-540.
  • Hambly, C., Simpson, C.A., McIntosh, S., Duncan, J., Dalgleish G.D., and SPEAKMAN, J.R. (2007)
    Calorie-restricted mice that binge show less ability to compensate for reduced energy intake
    Physiology and Behaviour 95: 982-992.
  • SPEAKMAN, J.R. and Hambly, C. (2007)
    Starving for life – what animal studies can, and cannot, tell us about the use of caloric
    restriction to prolong human lifespan.
    Journal of Nutrition 137:1078-1086
  • Johnston, S., Grune, T., Bell, L., Murray, S., Souter, D., Erwin, S., Yearsley, J., Gordon, I.,
    Illius, A., Kyriazakis, I., SPEAKMAN, J.R. (2006)
    Having it all - historical energy intakes do not generate the anticipated trade-offs in fecundity.
    Proceedings of the Royal Society of London B: Biological Sciences
  • Hambly, C.and SPEAKMAN, J.R. (2005)
    Contribution of different mechanisms to compensation for energy restriction in the mouse.
    Obesity Research 13: 1548-1557
  • Selman, C., Phillips, T., Staib, J.L., Duncan, J.S., Leeuwenburgh, C., and SPEAKMAN, J.R.
    (2005)
    Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition
    Mechanisms of Ageing and Development. 126: 783-793