Metabolism, Brain Size, and Lifespan in Mammals

Also see:
Unsaturated Fats and Longevity
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Nutrition and Brain Growth in Chick Embryos
PUFA, Development, and Allergy Incidence
W.D. Denckla, A.V. Everitt, Hypophysectomy, & Aging

“A living cell requires energy not only for all its functions, but also for the maintenance of its structure.” -Albert Szent-Gyorgyi

“The length of the life-span, and of the period of youth or immaturity, is closely associated with the size of the brain, and the brain has a very high rate of metabolism. When something interferes with this very high metabolic rate, the consequences may be instantanteous,* or developmental, or chronic and degenerative, or even transgenerational. The issue of epilepsy centers on questions of brain metabolism, and so it has all of those dimensions.” -Ray Peat, PhD

“Besides the observation of greater oxygen consumption in the low fat animals, and high protein tum-over in calorie restricted animals, there are observations in a variety of organisms associating a higher metabolic rate with greater longevity. While most longevity studies of flies involved altering the temperature of their environment, studies of differences of metabolic rate at a given temperature have in several cases found greater longevity in the high metabolizers. A study of 18 strains of mice found a clear association between a higher metabolic rate and greater longevity.(1) Recent studies (e.g., Joseph Graves’) are showing similar associations in
-Ray Peat, PhD

“Maintaining a high rate of oxidative metabolism, without calorie restriction, retards the accumulation of PUFA, and a high metabolic rate is associated with longevity. An adequate amount of sugar maintains both a high rate of metabolism, and a high respiratory quotient, i.e., high production of carbon dioxide.” -Ray Peat, PhD

“Another factor involved in developing a large brain is the metabolic rate, which is closely associated with the temperature…In birds and mammals, longevity generally corresponds to brain size and metabolic rate.” -Ray Peat, PhD

“They are advancing a myth about human nature, so I will advance a counter-myth. At the time people were growing their large brains they lived in the tropics. I suggest that in this time before the development of grain-based agriculture, they ate a diet that was relatively free of unsaturated fats and low in iron–based on tropical fruits. I suggest that the Boskop skull from Mt. Kilimanjaro was representative of people under those conditions, and that just by our present knowledge of the association of brain size with longevity, they–as various “Golden Age” myths claim–must have had a very long life-span. As people moved north and developed new ways of living, their consumption of unsaturated fats increased, their brain size decreased, and they aged rapidly. Neanderthal relics show that flaxseed was a staple of their diet.” -Ray Peat, PhD

“It has been observed that the ratio of brain weight to body weight corresponds directly to longevity. The brain has a nourishing, trophic influence on other tissues. A stable, efficient brain is an anti-stress agent. The hormones of stress age various tissues, including connective tissue. Good nutrition, including the anti-stress substances found in certain foods, will simultaneously optimize intelligence and increase the healthy life span. Congenital defects are increased by stress and poor nutrition during pregnancy and, conversely, reduced by good nutrition hormone supplementation and stress reduction.” -Ray Peat, PhD

“The brain has a high rate of oxidative metabolism, and so it forms a very large proportion of the carbon dioxide produced by an organism. It also governs, to a great extent, the metabolism of other tissues, including their consumption of oxygen and production of carbon dioxide or lactic acid. Within a particular species, the rate of oxygen consumption increases in proportion to brain size, rather than body weight. Between very different species, the role of the brain in metabolism is even more obvious, since the resting metabolic rate corresponds to the size of the brain. For example, a cat’s brain is about the size of a crocodile’s, and their oxygen consumption at rest is similar, despite their tremendous difference in body size.” -Ray Peat, PhD

Q Rev Biol. 1983 Dec;58(4):495-512.
Energy metabolism, brain size and longevity in mammals.
Hofman MA.
The mathematical relations between basal energy metabolism, brain size, and life span in mammals have been investigated. The evolutionary level of brain development, or encephalization (c), is a function both of brain weight (E) and of body weight (P) according to (formula; see text) Brain weight was found to be a linear function of the product of encephalization and basal metabolic rate. The oxygen consumption of the brain (Mbrain) is proportional to both encephalization and body weight according to (formula; see text) the ratio of metabolic rate in the cerebral cortex to that in the brain as a whole depends solely upon the degree of encephalization and is independent of the size of the animal. The maximum potential life span of a mammal was found to be proportional to the product of its degree of encephalization and the reciprocal of its metabolic rate per unit weight. Life span may be regarded as the algebraic sum of two components: (1) a deduced somatic component (Lb) inversely related to the basal metabolic rate per unit weight, and (2) an encephalization component (Le) related directly to the evolutionary increase of relative brain size.

Experimental Gerontology Volume 2, Issue 3, August 1967, Pages 173–182
Relation of lifespan to brainweight, bodyweight, and metabolic rate among inbred mouse strains
John B. Storer
Mean values for lifespan, brainweight, bodyweight, and metabolic rate were determined for male and female mice in 18 different inbredstrains. No significant correlation between means for log lifespan and log brainweight, log lifespan and log bodyweight, or log brainweight and log bodyweight could be demonstrated. The mean metabolic rate was significantly positively correlated with longevity in both sexes. A component of metabolic rate which is independent of body size may also be positively correlated with longevity.The findings contrast sharply with the between-species correlations of these variables. Possible reasons for this disparity are discussed.

Biol Lett. 2006 December 22; 2(4): 557–560.
Metabolic costs of brain size evolution
Karin Isler* and Carel P van Schaik
In the ongoing discussion about brain evolution in vertebrates, the main interest has shifted from theories focusing on energy balance to theories proposing social or ecological benefits of enhanced intellect. With the availability of a wealth of new data on basal metabolic rate (BMR) and brain size and with the aid of reliable techniques of comparative analysis, we are able to show that in fact energetics is an issue in the maintenance of a relatively large brain, and that brain size is positively correlated with the BMR in mammals, controlling for body size effects. We conclude that attempts to explain brain size variation in different taxa must consider the ability to sustain the energy costs alongside cognitive benefits.

Individuals within a strain of mice were found to vary considerably in their metabolic rate. The 25% of the mice with the highest rate used 30% more energy (per gram of body weight) than the 25% with the lowest metabolic rate, and lived 36% longer (Speakman, et al., 2004). -Ray Peat, PhD

Aging Cell. 2004 Jun;3(3):87-95.
Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer.
Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P, Krol E, Jackson DM, Johnson MS, Brand MD.
Two theories of how energy metabolism should be associated with longevity, both mediated via free-radical production, make completely contrary predictions. The ‘rate of living-free-radical theory’ (Pearl, 1928; Harman, 1956; Sohal, 2002) suggests a negative association, the ‘uncoupling to survive’ hypothesis (Brand, 2000) suggests the correlation should be positive. Existing empirical data on this issue is contradictory and extremely confused (Rubner, 1908; Yan & Sohal, 2000; Ragland & Sohal, 1975; Daan et al., 1996; Wolf & Schmid-Hempel, 1989]. We sought associations between longevity and individual variations in energy metabolism in a cohort of outbred mice. We found a positive association between metabolic intensity (kJ daily food assimilation expressed as g/body mass) and lifespan, but no relationships of lifespan to body mass, fat mass or lean body mass. Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein-3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest – supporting the ‘uncoupling to survive’ hypothesis.

FASEB J. 14, A757
Living fast and dying old: cross sectional variation in daily energy expenditure is positively linked to lifespan in female mice.
Speakman, J. R.; Snart, S.; Selman, C.; McLaren, J. S.; Redman, P.; Krol, E.; Jackson, D. M.; Johnson, M. S.
Inter-relationships between metabolism and longevity are confused. On one hand, inter-specific studies point to a strong negative relationship. Yet comparisons across classes yield the opposite trend. No previous studies have examined the consequences for lifespan of intraspecific variations in energy expenditure of animals living in a constant environment. Here, we report such a study in a group of 42 female MF1 mice. Between 6 and 13 months of age we monitored food intake, daily energy expenditure and assimilation efficiency. After 13 months of age, the mice were monitored daily until they died. We sought relationships between lifespan and the traits measured when the mice were 6-13-months-old. Contrary to expectations there were significant positive relationships between lifespan and daily energy expenditure, residual energy expenditure and metabolic intensity (energy expenditure per gram body mass). In this cohort of mice, living fast was associated with dying more slowly.

J Nutr. 2002 Jun;132(6 Suppl 2):1583S-97S.
Living fast, dying when? The link between aging and energetics.
Speakman JR, Selman C, McLaren JS, Harper EJ.
The idea that aging should be linked to energy expenditure has a long history that can be traced to the late 1800s and the industrial revolution. Machines that are run fast wear out more quickly, so the notion was born that humans and animals might experience similar fates: the faster they live (expressed as greater energy expenditure), the sooner they die. Evidence supporting the “rate-of-living” theory was gleaned from the scaling of resting metabolism and life span as functions of body mass. The product of these factors yields a mass-invariant term, equivalent to the “amount of living.” There are at least four problems with this evidence, which are summarized and reviewed in this communication: 1) life span is a poor measure of aging, 2) resting metabolism is a poor measure of energy expenditure, 3) the effects are confounded by body mass and 4) the comparisons made are not phylogenetically independent. We demonstrate that there is a poor association between resting metabolic rate (RMR) and daily energy expenditure (DEE) measured using the doubly labeled water (DLW) method at the level of species. Nevertheless, the scaling relation between DEE and body mass still has the same scaling exponent as the RMR and body mass relationship. Thus, if we use DEE rather than RMR in the analysis, the rate-of-living ideas are still supported. Data for 13 species of small mammal were obtained, where energy demands by DLW and longevity were reliably known. In these species, there was a strong negative relationship between residual longevity and residual DEE, both with the effects of body mass removed (r(2) = 0.763, F = 32.1, P < 0.001). Hence, the association of energy demands and life span is not attributed to the confounding effects of body size. We subjected these latter data to an analysis that extracts phylogenetically independent contrasts, and the relationship remained significant (r(2) = 0.815, F = 39.74, P < 0.001). Small mammals that live fast really do die young. However, there are very large differences between species in the amounts of living that each enjoy and these disparities are even greater when other taxa are included in the comparisons. Such differences are incompatible with the “rate-of-living” theory. However, the link between energetics and aging across species is reconcilable within the framework of the “free-radical damage hypothesis” and the “disposable soma hypothesis.” Within species one might anticipate the rate-of-living model would be more appropriate. We reviewed data generated from three different sources to evaluate whether this were so, studies in which metabolic rate is experimentally increased and impacts on life span followed, studies of caloric restriction and studies where links between natural variation in metabolism and life span are sought. This review reveals that there might be contrasting effects of resting and nonresting energy expenditure on aging, with increases in the former being protective and increases in the latter being harmful.

Many dog owners are aware that small dogs eat much more food in proportion to their size than big dogs do. And small dogs have a much greater life expectancy than big dogs, in some cases about twice as long (Speakman, 2003). -Ray Peat, PhD

Aging Cell. 2003 Oct;2(5):265-75.
Age-related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy.
Speakman JR, van Acker A, Harper EJ.
We measured body composition and resting metabolic rates (RMR) of three dog breeds (Papillons, mean body mass 3.0 kg (n = 35), Labrador retrievers, mean body mass 29.8 kg (n = 35) and Great Danes, mean body mass 62.8 kg (n = 35)) that varied between 0.6 and 14.3 years of age. In Papillons, lean body mass (LBM) increased with age but fat mass (FBM) was constant; in Labradors, both LBM and FBM were constant with age, and in Great Danes, FBM increased with age but LBM was constant. FBM averaged 14.8% and 15.7% of body mass in Papillons and Labradors, respectively. Great Danes were leaner and averaged only 10.5% FBM. Pooling the data for all individuals, the RMR was significantly and positively associated with LBM and FBM and negatively associated with age. Once these factors had been taken into account there was still a significant breed effect on RMR, which was significantly lower in Labradors than in the other two breeds. Using the predictive multiple regression equation for RMR and the temporal trends in body composition, we modelled the expenditure of energy (at rest) over the first 8 years of life, and over the entire lifespan for each breed. Over the first 8 years of life the average expenditure of energy per kg LBM were 0.985, 0.675 and 0.662 GJ for Papillons, Labradors and Great Danes, respectively. This energy expenditure was almost 60% greater for the smallest compared with the largest breed. On average, however, the life expectancy for the smallest breed was a further 6 years (i.e. 14 years in total), whereas for the largest breed it was only another 6 months (i.e. 8.5 years in total). Total lifetime expenditure of energy at rest per kg LBM averaged 1.584, 0.918 and 0.691 GJ for Papillons, Labradors and Great Danes, respectively. In Labradors, total daily energy expenditure, measured by the doubly labelled water method in eight animals, was only 16% greater than the observed RMR. High energy expenditure in dogs appears positively linked to increased life expectancy, contrary to the finding across mammal species and within exotherms, yet resembling observations in other intra-specific studies. These contrasting correlations suggest that metabolism is affecting life expectancy in different ways at these different levels of enquiry.

J Exp Biol. 2005 May;208(Pt 9):1717-30.
Body size, energy metabolism and lifespan.
Speakman JR.
Bigger animals live longer. The scaling exponent for the relationship between lifespan and body mass is between 0.15 and 0.3. Bigger animals also expend more energy, and the scaling exponent for the relationship of resting metabolic rate (RMR) to body mass lies somewhere between 0.66 and 0.8. Mass-specific RMR therefore scales with a corresponding exponent between -0.2 and -0.33. Because the exponents for mass-specific RMR are close to the exponents for lifespan, but have opposite signs, their product (the mass-specific expenditure of energy per lifespan) is independent of body mass (exponent between -0.08 and 0.08). This means that across species a gram of tissue on average expends about the same amount of energy before it dies regardless of whether that tissue is located in a shrew, a cow, an elephant or a whale. This fact led to the notion that ageing and lifespan are processes regulated by energy metabolism rates and that elevating metabolism will be associated with premature mortality–the rate of living theory. The free-radical theory of ageing provides a potential mechanism that links metabolism to ageing phenomena, since oxygen free radicals are formed as a by-product of oxidative phosphorylation. Despite this potential synergy in these theoretical approaches, the free-radical theory has grown in stature while the rate of living theory has fallen into disrepute. This is primarily because comparisons made across classes (for example, between birds and mammals) do not conform to the expectations, and even within classes there is substantial interspecific variability in the mass-specific expenditure of energy per lifespan. Using interspecific data to test the rate of living hypothesis is, however, confused by several major problems. For example, appeals that the resultant lifetime expenditure of energy per gram of tissue is ‘too variable’ depend on the biological significance rather than the statistical significance of the variation observed. Moreover, maximum lifespan is not a good marker of ageing and RMR is not a good measure of total energy metabolism. Analysis of residual lifespan against residual RMR reveals no significant relationship. However, this is still based on RMR. A novel comparison using daily energy expenditure (DEE), rather than BMR, suggests that lifetime expenditure of energy per gram of tissue is NOT independent of body mass, and that tissue in smaller animals expends more energy before expiring than tissue in larger animals. Some of the residual variation in this relationship in mammals is explained by ambient temperature. In addition there is a significant negative relationship between residual lifespan and residual daily energy expenditure in mammals. A potentially much better model to explore the links of body size, metabolism and ageing is to examine the intraspecific links. These studies have generated some data that support the original rate of living theory and other data that conflict. In particular several studies have shown that manipulating animals to expend more or less energy generate the expected effects on lifespan (particularly when the subjects are ectotherms). However, smaller individuals with higher rates of metabolism live longer than their slower, larger conspecifics. An addition to these confused observations has been the recent suggestion that under some circumstances we might expect mitochondria to produce fewer free radicals when metabolism is higher–particularly when they are uncoupled. These new ideas concerning the manner in which mitochondria generate free radicals as a function of metabolism shed some light on the complexity of observations linking body size, metabolism and lifespan.

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