Angelos C. Economos

Mitochondrial role in cell aging

The experimental studies on the mitochondria of insect and mammalian cells are examined with a view to an analysis of intrinsic mitochondrial senescence, and its relation to the age-related changes in other cell organelles. The fine structural and biochemical data support the concept that the mitochondria of fixed postmitotic cells may be the site of intrinsic aging because of the attack by free radicals and lipid peroxides originating in the organelles as a by-product of oxygen reduction during respiration. Although the cells have numerous mechanisms for counteracting lipid peroxidation injury, there is a slippage in the antioxidant protection. Intrinsic mitochondrial aging could thus be considered as a specific manifestation of oxygen toxicity. It is proposed that free radical injury renders an increasing number of the mitochondria unable to divide, probably because of damage to the lipids of the inner membrane and to mitochondrial DNA.

Favorable effects of the antioxidants sodium and magnesium thiazolidine carboxylate on the vitality and life span of Drosophila and mice

Abstract We have investigated the effects of two antioxidants, sodium and magnesium L-thiazolidine-4-carboxylate (NaTC, MgTC), on vitality and life span of female mice and male Drosophila melanogaster (fruit flies). NaTC or MgTC was added to the food medium of populations of flies (about 170 flies each) at a 0·2% concentration from the 26th day of their adult life, whereas MgTC was given to 39 mice at the concentration of 0·07% in their standard chow, starting at the age of 23 months. The antioxidant treatment resulted in mean life span increases of 8 and 14% in flies treated with NaTC and MgTC, respectively. Apparently, the maximum life span was similarly increased as reflected in the ages of the longest lived individuals, although much larger populations should be studied for statistical evaluation. It seems that mouse aging was also influenced by antioxidant treatment, although to a lesser degree than Drosophila aging. This is suggested by our observation that mice given MgTC had a median life span about 7% longer than the control animals. Vitality of middle aged flies (assessed by measuring their mating capacity) receiving MgTC was increased considerably in comparison with the controls. The mean body weights of groups of treated flies and mice were not different from those of the controls and the food intake was about the same for control and treated mice. Therefore, the favorable effects of the antioxidants MgTC and NaTC on mortality kinetics of flies and mice and on the vitality of flies cannot be explained as the outcome of caloric restriction. In our opinion, the favorable results which are consistently associated with the use of NaTC, MgTC or other sulphur-containing substances are related to their free radical scavenger action. In accordance with this concept, the above substances may be effective in reducing the rate of the aging process.

Antioxidants, metabolic rate and aging in Drosophila.

In line with the (metabolic) rate-of-living theory of aging, previous work from this laboratory showed that the life-prolonging effect of the antioxidant thiazolidine carboxylic acid (TCA) in Drosophila was paralleled by a similar reduction of the oxygen consumption rate of the flies. To assess the generality of this phenomenon, several life-prolonging antioxidants were dietarily administered to the flies (in standard medium with 1% w/v of tocopherol-stripped corn oil) and their effects on metabolic rate and life span were determined. Respiration rate of groups of continuously agitated flies was measured in the Gilson respirometer. The studied antioxidants were as follows: (the numbers in parentheses are consecutively the antioxidant concentration in the medium in % wt/vol.; mean life span in days; and metabolic rate in microliter O2/mg fly per 24 h): vitamin E (0.4; 46.3; 58.5); 2,4-dinitrophenol (0.1; 45.7; 66.2); nordihydroguaiaretic acid (0.5; 45.6; 69.1); thiazolidine carboxylic acid (0.3; 53.1; 55.8); and control with no antioxidant added (0; 40.7; 73.3). All of these antioxidants at the tested concentrations reduced oxygen consumption rate and increased mean life span; there was a significant negative linear correlation (r = -0.87) between mean life span and metabolic rate. These data suggest that some antioxidants may inhibit respiration rate in addition to their protective effect against free radical-induced cellular damage.

Review of cell aging in Drosophila and mouse

In this review we evaluate Minot’s hypothesis that cellular aging and death of metazoan animals are the result of cell differentiation. The fine structural data suggest that aging in Drosophila is reflected in cytoplasmic organelle loss with accompanying age pigment accumulation. Apparently, a progressive disorganization of fixed postmitotic cells plays a key role in the aging process of fruit flies. In aging mice, electron microscopic studies suggest that primary senescent deterioration takes place also in fixed postmitotic cells. Intermitotic cells appear to undergo only minimal changes, while many fast dividing cells are not affected by aging. We conclude that Minot’s hypothesis is consistent with reviewed evidence on cellular aging mechanisms in Drosophila and mouse. Theoretical support for the hypothesis is derived from a systems analysis of organism-environment interaction and the consequences of cellular organization in flies and mice.

On the origin of biological similarity

The principles of biological similarity have not been adequately defined. Previous studies have not been fully successful, mainly because the search for such principles centered around the idea that a few of them would apply to all animals, just as Newtons principles of mechanical similarity apply to all inanimate objects. However, this is not possible, so that the search has led up a number of blind alleys, ending with a failure to provide a fundamental and unified explanation—as contrasted with empirical justification—for the scaling of basal metabolic rate of many kinds of animals (e.g. mammals, birds, fish, certain small metazoa) according to a 34-power of body mass, M, rather than as M23 (“surface law”) or M1·0; moreover, none of the previous theories can account for the fact that other kinds of animals (e.g. insects, snakes, hibernating mammals) do not obey the M34-rule. Two basic characteristics of all animals are that in the water they are on “the verge of floating” and that movement is interwoven with the nature of animal life itself. These observations lead to the principle of constancy of body density (ρ ⋍ 1) and to the principle of similarity in some defined sense of the muscular apparatus—the universal generator of movement—across species, but only within classes of animals that have evolved similar methods of locomotion. Because muscle tissues are subject to elastic (“spring-type”) contraction forces, a general elastic similarity principle holds for muscle diameter, d, vs. a linear body dimension, L, i.e., d2 ∝ L3 (Galileo-Rashevsky principle; this principle is valid also for the dimensions of the trunk of animals without exoskeleton subject to a gravitational load, e.g. for land mammals but not for sea mammals). A final principle which, combined with the above, leads to the M34-rule for muscle-power generation, is that time is scaled as the linear dimension, T ∝ L (in contrast to Newtons second principle of mechanical similarity for physical objects, T ∝ L12). This principle was introduced in the past either as an arbitrary assumption (Lambert & Teissier) or based on the empirical finding of constancy of muscle shortening velocity (∝ LT across mammalian species (Hill-McMahon). However, this principle cannot be valid for the classes of animals which do not obey the M34-rule. This principle is derived here from the more fundamental principle of constancy, across similar species, of mechanical stress (force over cross-section) endured by contracting muscles. In species such as snakes, however, in which locomotion is generated in a different way, friction forces assume an important role and scaling of time as with mechanical similarity, T ∝ L12, is obtained by assuming a similar velocity of the animals along their axis as size increases; using this scaling, the deviation of snakes from the M34-rule is explained. Interestingly, though, such scaling may have limited the maximal body size of snakes. A yet different principle seems to be operating in insects, leading to the scaling: T ∝ L−13 and a faster than body mass increase of basal metabolic rate. Finally, neither heat loss nor surface-related transport appear to be limiting and setting factors for metabolic rate—indeed “surface arguments” are entirely unbased. Only in some situations where the M34-rule is not obeyed because of heat loss considerations (e.g. dogs adapted to the tropics or to the arctic cold) is a surface argument relevant.

Brain-Life Span Conjecture: a Reevaluation of the Evidence

Empirical evidence for the conjecture that brain weight of mammals is a better predictor of life span than is body weight, is reexamined and evaluated in this paper. The original evidence was that for 63 mammalian species, log brain weight explained 79% of the log life span variance, whereas log body weight explained only 60%; thus, the correlation coefficient rbr for the linear regression of the log life span on log brain weight was 0.88, whereas the correlation coefficient rb for the regression of log life span on log body weight was 0.77. From data on 40 mammalian species (including three primates), we found rbr = 0.81 and rb = 0.75; from data on 35 primate species, we found rbr = 0.68 and rb = 0.65. Correlation coefficients rliv, radr for the regression of log life span on log liver weight or log adrenal weight, respectively, were rliv = 0.78 and radr = 0.81 for the same 40 mammalian species. We conclude that brain weight appears to be a slightly better predictor of life span than body weight but not better than adrenal weight. One primary reason why body weight is a poorer predictor of life span may be a result of its wider range of values compared with brain and adrenal weights.

Kinetics of metazoan mortality

Abstract In contrast to the well-known generalization that force of mortality and probability of death in aging populations increase exponentially with age (‘Gompertzs law’), analysis of mortality kinetics data from a variety of metazoan species that have now become available indicates that Gompertzs law is only an approximation, not valid over a certain terminal part of the lifespan, during which force of mortality levels off. A previously introduced simple paradigm which describes mortality kinetics more accurately is analyzed mathematically; its applicability and usefulness for experimental gerontology are illustrated. It is shown mathematically that this paradigm is equivalent with Gompertzs law over the initial age range in which this law is generally valid.

On structural theories of basal metabolic rate.

Abstract Because cells and organisms interface with the environment through surfaces, their design should be governed by surface laws. Yet, basal metabolic rate is not proportional to the 0·67-power of body mass (surface law) but to the 0·75-power of body mass. From the many theories that have derived a surface law, Teissiers dimensional analysis theory was probably the neatest. However, the surface law has been empirically invalidated. Moreover, Teissier assumed that times in the prototype animal and a similar one with different size are in the same ratio as their linear sizes. This is incorrect, however, because heart rates, being inverses of times, should be proportional to the 1 3 -power of body mass—but are proportional to the 1 4 -power of body mass, which is consistent with a 0·75-power law of basal metabolic rate. McMahons recent attempt to explain the deviation of the empirical law from a surface law based entirely on structural considerations, is critically examined. It does not appear that purely structural considerations could explain the deviation between the empirical 0·75-law of basal metabolic rate and the surface law.

The largest land mammal

Abstract Although a lower limit to size of land mammals, about 2·5 g, was established over 30 years ago, no definite upper limit has been proposed. The largest mammal known to have lived on land was the Baluchitherium, with a body mass of about 20 000 kg. In this paper, I show that gravity imposes an upper limit to size of land mammals. This limit results from the metabolic cost of gravity, which increases with body mass; therefore, the larger the body mass of an animal the smaller is the gravitational field intensity that can be tolerated by the animal. From data on gravitational tolerance of a number of mammalian species, it is shown that the size of the land mammal that can not tolerate more than terrestrial gravity is approximately 20 000 kg.

Taxonomic differences in the mammalian life span-body weight relationship and the problem of brain weight.

Despite the highly significant correlation between brain and body weight throughout the entire mammalian class, there are consistent differences between rodents, higher primates, carnivores, and ungulates. Primates have larger brains than carnivores of equal size, while rodents have smaller brains, and ungulates have similar-sized brains as carnivores with the same body weight. Further, life span correlates well with body weight for all mammals together (over 150 species), although there are large and consistent interorder differences. For a given body weight, carnivores have a shorter life span than primates, one as long as rodent, and one longer than ungulates. These differences in life span are not matched by the differences in brain weight. Therefore, the conjecture that brain size is a determinant of life span is not valid.