Energy Metabolism, Nutrition and Ageing

Roger J.M. McCarter

Department of Physiology, University of Texas Health Science Center, USA

Abstract. Energy metabolism and nutrition have long been suggested to play a role in ageing
processes, in age-related disease and in the health of the elderly. This review addresses new
insights arising from selected studies of the interplay of these factors. Data on overfeeding and
underfeeding in young versus elderly men and women demonstrate a deficit with age in the
ability to regulate energy balance. They also indicate that current values of Recommended
Daily Allowances of caloric intake underestimate the needs of the elderly. The studies suggest
that diminished capacity of energy metabolism with age may have a nutritional component and
the involvement of the central nervous system. The contribution of peripheral tissues is
suggested by studies of mitochondrial DNA isolated from tissues of humans and rodents. The
studies demonstrate age-related and disease-related increases in rates of mutation in some but
not all tissues. The further involvement of mitochondrial dysfunction in ageing is suggested by
data on oxidative free radical production in mitochondria of birds versus rodents. These elegant
studies indicate greatly reduced rates of free radical production in mitochondria of long-lived
birds versus short-lived rodents. They further demonstrate that Complex I of the respiratory
chain may be a major factor in these species-specific effects. Restriction of caloric intake
(dietary restriction, DR) is the only manipulation known to consistently extend lifespan in a
wide variety of species. Previous work shows that extension of lifespan in DR is not necessarily
related to reduced metabolic rate per unit metabolic mass. More recent work in exercising DR
rats demonstrates consistently high daily metabolic rates together with extended lifespan.
Other studies also show altered characteristics of fuel use in DR, indicating the ability of DR
rats to maintain appropriate rates of fuel use under conditions less damaging to the organism.
All of these new approaches to the interaction of nutrition, energy expenditure and ageing
suggest that regulation of energy balance and the characteristics of fuel use play significant
roles in ageing and in age-related disease.

Introduction metabolic rate per se may govern the interplay

Just over a century ago a scientific renaissance between nutrition, energy metabolism and ageing.
resulted in the discovery of many fundamental laws The review focuses on selected recent research
of nature, including formulation of the principles demonstrating that characteristics of fuel use,
underlying electricity and magnetism and the laws rather than intensity of fuel use, may link these
of thermodynamics. It was in this environment that quantities. The studies were conducted in intact
Max Rubner decided he had discovered “the unity of organisms (humans and rodents) and in isolated
a great law” governing the lifespan of living mitochondria (in humans, rodents and birds) the
creatures [l].His data on the oxygen consumption of organelles having major responsibility for energy
domestic animals suggested that sexually mature transduction. More general discussions of energy
animals have a fixed lifetime metabolic potential, ie. use in ageing provide a broader view of the field [ 5 , 6 ] .
that all adult organisms consume about the same
amount of energy per unit of mass over their Energy Balance
lifespan. Subsequent experiments, notably by Loeb Relative constancy of body weight over the adult
and Northrop [21 and Pearl [31 resulted in lifespan is determined by balancing energy input
formulation of the “Rate of Living“ theory of ageing, (nutrient intake) with energy output (totalenergy
suggesting that “duration of life.....varies inversely expenditure, or metabolic rate) over a sustained
as the rate of living during its continuance...” [31. period of time. A constant daily energy expenditure
This view has played a pivotal role in later theories in the face of decreased nutrient input will lead to
of ageing, with evidence both in support of and loss of weight, to a decrease in amount of
against it. In particular there is no strong evidence metabolically active tissue and in turn to a decrease
in homeothermic animals in support of the original in metabolic rate. Mechanisms involved in balancing
views 141. energy input and output have not been identified.
Despite the controversies, however, few The work of Roberts and Saltzman [7] strongly
gerontologists would deny the probable importance suggests, however, that ageing in humans is
of nutrition and energy metabolism in ageing and in associated with decreased ability t o regulate energy
age-related disease. The goal of this review is to balance. These studies in young adult and elderly
discuss recent evidence that processes other than men involved measurement of body weight and food
intake following several weeks of both underfeeding
and overfeeding. Similar losses or gains of body
Correspondence to Dr R. McCarter, Department of weight occurred during controlled under- and
Physiology, University of Texas Health Science Center, San overfeeding, respectively in the young adults and in
Antonio, Texas 78284, USA. the elderly. Following these periods, young
Email: MCCARTER@UTHSCSA.edu

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individuals allowed to eat ad libitum increased or addressed the apparent paradox (at least for
decreased food intake appropriately, resulting in a adherents of the Rate of Living theory of ageing) of
return to the pre-trial bodyweight. In contrast, the great longevity of birds which also exhibit high
elderly individuals permitted ad libitum eating did specific metabolic rates (SMR). The paradox lies in
not make appropriate adjustments in food intake, the inverse relation which exists, according to the
exhibiting sustained losses or gains of body weight. Rate of Living theory, between longevity and
The experiments demonstrated a differential effect metabolic rate per unit mass ( S M R ) .
in young versus elderly of change of energy intake Baja and colleagues have isolated mitochondria
on resting energy expenditure (REE): Young from brain, lung and liver tissues of rats (of
individuals exhibited a significantly greater maximum lifespan about 4 years) and pigeons
increase in REE for a given change in energy intake (having maximum lifespan of about 35 years).
than did elderly individuals. Data on total energy Despite having significantly greater rates of resting
expenditure (TEE) also indicated that current whole body oxygen consumption and mitochondrial
Recommended Daily Allowances for calorie intake respiratory rates, the rates of mitochondrial free
may be inadequate in the case of the elderly. radical production were 2-4 times lower in pigeon
These provocative results suggest that problems than in rat tissues. Indeed, the rates of free radical
of energy use in ageing may be due in part to production per unit oxygen consumption were one
decreased ability to maintain energy balance. order of magnitude lower in pigeon than in rat
Decrease in metabolic rate with age and in mitochondria. Free radical ‘leak‘ from the
particular loss of muscle mass with age may respiratory chain was significantly less in pigeon
therefore involve central mechanisms as well as than in rat mitochondria [13]. Further studies of
peripheral cellular mechanisms. The data warrant this group demonstrated that, in heart
in depth investigation in animal models for mitochondria, Complexes I and I11 are the principal
identification of mechanisms involved. generators of reactive hydrogen peroxide.
Differences in free radical generation between heart
Mitochondrial DNA mitochondria of rats and birds were mainly
Direct involvement of cellular organelles in the attributable to species-variations in Complexes I
age-related decline of energy metabolism is and I11 in the heart [141.
indicated by studies of mutations in mitochondrial The recent work of these authors [15] addresses
DNA (mtDNA). In a n extensive series of studies another paradox: namely the fact that lifelong
Linnane and colleagues [eg. 8-11] have examined exercise is not usually associated with a significant
rearrangements of mtDNA in a variety of tissues in shortening of lifespan [16], in apparent
humans and rats of various ages. Their data indicate contradiction to predictions of the Rate of Living
random mutations of mtDNA in cells throughout theory. Mitochondria isolated from the brains and
life, that these mutations accumulate in tissues with hearts of rats and pigeons exhibited similar levels of
age, that the rates of accumulation are tissue- and free radical production from Complex I in both
species-specific and that some age-associated states 4 (resting) and 3 (uncoupled, or maximum
diseases are correlated with the presence of mtDNA rate), a possible consequence of greatly decreased
mutations. These workers hypothesise that the free radical leaks from Complex I in state 3
accumulated mutations lead to disruption of usual respiration.
mitochondrial function, to a n ‘energy mosaic’ of cells
of different bioenergetic capacity, and that this loss The results of all these studies are consistent
of energy transduction capacity, in turn, is a basis of with the Free Radical theory of ageing, based on the
senescence and age-related disease. primary importance of tissue degeneration due to
accumulated free radical damage. The results
In support of these ideas the authors have demonstrate also that the characteristics of fuel use,
demonstrated a strong correlation between rather than the intensity of fuel use may determine
decreased cytochrome oxidase activity and extent of the rate of ageing.
mtDNA mutations in human skeletal muscle fibers
with age [lo]. They have also demonstrated Dietary Restriction
amelioration of the effects of oxidative stress using Restriction of caloric intake is the only
coenzyme QlO as a redox agent to ‘re-energise’ manipulation known to consistently retard ageing
issues 181. The extent to which the decline of processes in homeothermic animals [17]. Extensive
oxidative metabolism with age in some tissues is due studies in laboratory rodents have demonstrated
to mtDNA mutations is not known, however. Studies that this dietary restriction (DR) not only extends
of this group, by Aiken et al. [121 and others longevity but also delays or prevents age-related
certainly suggest the possible involvement of pathology and slows functional decline [181. Equally
mtDNA in ageing processes. extensive studies of the interaction of DR and
energy metabolism [191 have demonstrated that
Mitochondrial Oxidative Free Radical metabolic rate decreases following the initiation of
Production DR to a n extent greater than can be explained by a
Further demonstration of the possible decrease in metabolic mass, ie. DR results in a
involvement of mitochondrial energetics in ageing decrease in specific metabolic rate (SMR). It was
processes has come from the interesting work of logical therefore for George Sacher [20] to suggest
B a j a and colleagues [eg. 13-151. These authors have that DR slows ageing processes as a consequence of

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Roger McCarter convened the Symposium on McCarter RJM. Efects of dietary restriction on
Nutrition, Energy Expenditure and Ageing, metabolic rate and ageing.
World Congress of Gerontology, Adelaide,
~ ~ ~ 997.
~ The
~ following
~ l papers
i ~ ulere
, McCarter RJM. Energy metabolism, nutrition and
presented. ageing.

Barja G. Mitochondrial function across Roberts SB. Factors affecting energy balance in
phylogenetic lines and the rate of living theory of young and Old men and women*
ageing.
Linnane AW. Mitochondria1 dysfunction in ageing
and disease.

59 World Congress of Gerontology, Adelaide, Australia, 1997