Increased Metabolic Rate May Lead to Accelerated Aging
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"Increased EE and ATP turnover increase free radical formation, and this is proposed as a mechanism for accelerated aging and increased mortality" (I recall from early HIV research that HIV+ have increased metabolic rates)
Findings from new study may explain why low-calorie diets are beneficial for human health
A recent study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM) found that higher metabolic rates predict early natural mortality, indicating that higher energy turnover may accelerate aging in humans.
Higher energy turnover is associated with shorter lifespan in animals, but evidence for this association in humans is limited. To investigate whether higher metabolic rate is associated with aging in humans, this study examined whether energy expenditure, measured in a metabolic chamber over 24 hours and during rest predicts natural mortality.
"We found that higher endogenous metabolic rate, that is how much energy the body uses for normal body functions, is a risk factor for earlier mortality," said Reiner Jumpertz, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases in Phoenix, Ariz., and lead author of the study. "This increased metabolic rate may lead to earlier organ damage (in effect accelerated aging) possibly by accumulation of toxic substances produced with the increase in energy turnover."
"It is important to note that these data do not apply to exercise-related energy expenditure," added Jumpertz. "This activity clearly has beneficial effects on human health."
In this study, researchers evaluated 652 non-diabetic healthy Pima Indian volunteers. Twenty four hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals and 240 underwent both measurements on separate days. Data for 24EE were collected in a respiratory chamber between 1985 and 2006 with a mean follow-up time of 11.1 years. RMR was evaluated using an open-circuit respiratory hood system between 1982 and 2006 with a mean follow-up time of 15.4 years.
During the study period, 27 study participants died of natural causes. Researchers found that as energy expenditure increased, there was also an increase in risk for natural mortality.
"The results of this study may help us understand some of the underlying mechanisms of human aging and indicate why reductions in metabolic rate, for instance via low calorie diets, appear to be beneficial for human health," said Jumpertz.
Other researchers working on the study include: Robert Hanson, Maurice Sievers, Peter Bennett, Robert Nelson and Jonathan Krakoff of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Phoenix, Ariz.
The article, "Higher energy expenditure in humans predicts natural mortality," appears in the June 2011 issue of JCEM.
Higher Energy Expenditure in Humans Predicts Natural Mortality
The Journal of Clinical Endocrinology & Metabolism June 1, 2011
Reiner Jumpertz, Robert L. Hanson, Maurice L. Sievers, Peter H. Bennett, Robert G. Nelson, and Jonathan Krakoff
Obesity and Diabetes Clinical Research Section (R.J., J.K.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016; and Diabetes Epidemiology and Clinical Research Section (R.L.H., M.L.S., P.H.B., R.G.N.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85014
Context: Higher metabolic rates increase free radical formation, which may accelerate aging and lead to early mortality.
Objective: Our objective was to determine whether higher metabolic rates measured by two different methods predict early natural mortality in humans.
Design: Nondiabetic healthy Pima Indian volunteers (n = 652) were admitted to an inpatient unit for approximately 7 d as part of a longitudinal study of obesity and diabetes risk factors. Vital status of study participants was determined through December 31, 2006. Twenty-four-hour energy expenditure (24EE) was measured in 508 individuals, resting metabolic rate (RMR) was measured in 384 individuals, and 240 underwent both measurements on separate days. Data for 24EE were collected in a respiratory chamber between 1985 and 2006 with a mean (sd) follow-up time of 11.1 (6.5) yr and for RMR using an open-circuit respiratory hood system between 1982 and 2006 with a mean follow-up time of 15.4 (6.3) yr. Cox regression models were used to test the effect of EE on natural mortality, controlled for age, sex, and body weight.
Results: In both groups, 27 natural deaths occurred during the study period. For each 100-kcal/24 h increase in EE, the risk of natural mortality increased by 1.29 (95% confidence interval = 1.00Ð1.66; P < 0.05) in the 24EE group and by 1.25 (95% confidence interval = 1.01Ð1.55; P < 0.05) in the RMR group, after adjustment for age, sex, and body weight in proportional hazard analyses.
Conclusions: Higher metabolic rates as reflected by 24EE or RMR predict early natural mortality, indicating that higher energy turnover may accelerate aging in humans.
Higher energy turnover is associated with shorter lifespan in animals, but evidence for this association in humans is limited. Over a century ago, the German physiologist Max Rubner linked body size and energy turnover with lifespan (1), and Benedict's mouse-elephant curve extended these findings by demonstrating that smaller animals expend relatively more energy per body mass and have a shorter life span than larger animals (2). The physiological underpinnings of the theory that lifespan is determined by a rate of living, however, are not clear. The free radical theory of aging proposes that aging is accelerated by the accumulation of cellular metabolites, in particular toxic free radicals (3). Free radicals in the form of reactive oxygen species (ROS) accumulate more quickly with higher metabolic rates and are responsible for various types of oxidative damage in the cell (4). To investigate the hypothesis that higher metabolic rate is associated with aging, we examined whether energy expenditure (EE), measured in a metabolic chamber over 24 h and during rest predicts natural mortality in nondiabetic Pima Indians from the Gila River Indian Community.
Subject characteristics of SG-1 and SG-2 are presented in Table 1. Causes of death in both SG-1 and SG-2 are listed in Table 2. Overall, 43 nonnatural deaths in SG-1 and 53 occurred in SG-2, whereas 27 natural deaths were ascertained in each study group. Death due to alcohol-related causes predominated in both groups. As shown in Supplemental Table 1 (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org), baseline characteristics did not differ between SG-1 and DS-1, although individuals in DS-1 were slightly older. In DS-2, individuals were also slightly older and had slightly higher fasting glucose levels compared with SG-2.
In proportional hazard models adjusted for age, sex, and body weight, higher 24EE increased the risk of natural mortality [hazard rate ratio (HRR) = 1.29 with 95% confidence interval (CI) = 1.00Ð1.66; P < 0.05 for each 100-kcal increase in 24 h] but not all-cause mortality [HRR = 1.06 (95% CI = 0.90Ð1.24); P = 0.47]. Additional adjustment for fasting glucose did not change the results. Bootstrap replicates revealed 496 of 1000 P values were below 0.05, with a median P value of 0.052. Likewise, RMR predicted natural mortality with HRR = 1.25 (95% CI = 1.01Ð1.54) and P = 0.04 for each 100-kcal increase in 24 h but not all-cause mortality [HRR = 0.97 (95% CI = 0.86Ð1.09); P = 0.56]. After bootstrapping, 506 of 1000 P values were below 0.05, with a median P value of 0.046. Results were similar for 24EE and RMR if FM and FFM were substituted for body weight in the models [HRR = 1.30 (95% CI = 1.00Ð1.67), P < 0.05; and HRR = 1.24 (95% CI = 1.00Ð1.54), P < 0.05]. Further adjustment for fasting glucose or 2-h glucose did not change the results for 24EE or RMR. However, SLEEP was not a predictor of either natural mortality [HRR = 1.00 (95% CI = 0.99Ð1.00); P = 0.89[ or all-cause mortality [HRR = 1.10 (95% CI = 0.94Ð1.30); P = 0.24].
To adjust for additional covariates, measures of EE were adjusted for age, sex, physical activity (for 24EE only), FM, and FFM in the larger cohorts as described above. After including the extracted residuals in a proportional hazard model for survival time, 24EE modestly predicted natural mortality with a HRR of 1.29 (95% CI = 0.99Ð1.68; P = 0.06) and RMR remained a significant predictor of natural mortality with a HRR of 2.30 (95% CI = 1.04Ð5.10; P < 0.05). Additional adjustment for fasting glucose did not change the results. However, SLEEP was still not a predictor of natural mortality [HRR = 1.14 (0.87Ð1.49); P = 0.35].
In this longitudinal study, we found that 24EE and RMR, measured on different days, predict natural mortality in Pima Indians. These results are consistent with previously described data for RMR in an older population (9). In the present study, EE was measured in a younger population, and two different measures of EE provided consistent results.
Increased EE and ATP turnover increase free radical formation, and this is proposed as a mechanism for accelerated aging and increased mortality (3). Furthermore, studies in animals indicate that reduced metabolic rate after caloric restriction has beneficial effects on lifespan (10). However, recent studies using knockout models of key antioxidant genes in the worm Caenorhabditis elegans and data from long-lived mouse models have produced inconsistent results, therefore calling this oxidative damage theory into question (11).
Importantly, studies in which energy turnover is willfully increased (via physical activity) demonstrate clear metabolic benefits (12). Therefore, our results do not apply to increased energy turnover due to exercise. This belief is supported by two recent reports showing that 1) excess fat intake (which increases metabolic rates) leads to increased ROS production, which links overnutrition to insulin resistance, whereas 2) transient elevations in ROS induced by physical exercise may be essential for training-induced insulin sensitivity (13, 14). Thus, a transient elevation of ROS, as seen during physical exercise, could have beneficial effects on human health, whereas sustained elevations in ROS due to higher metabolic rates as a consequence of macronutrient excess could be harmful. Recent experiments have shown that transgenic hypermetabolic mice with increased uncoupling from ectopically expressed uncoupling protein 1 live longer than their wild-type counterparts (15, 16). Despite higher metabolic rates, these mice show substantial reductions in mitochondrial ROS production (17). Together these data indicate that the effect of elevated metabolic rate on cell/organ damage over a lifespan needs to be viewed against the background of ROS production.
Because exams were performed at a young age, the number of natural deaths was low, allowing for a limited number of covariates in our regression analyses, which could result in some residual confounding (18). However, additional adjustments in larger cohorts and bootstrap analyses indicated that the results remained robust to further adjustments. Although causes of death were spread among many diagnoses, liver disease due to exogenous exposure was very common. This outcome might be expected in a cohort where early nontraumatic mortality is more likely to be due to long-term effects of exogenous exposures (such as alcohol). However, increased EE could explain greater susceptibility to liver disease in the setting of alcohol exposure. The combination of an exogenous toxin (such as alcohol) with the accumulation of free radicals could result in chronic low-grade damage by accrual of these metabolites and result in greater hepatic injury (19). It should be acknowledged that chronic alcohol use is known to increase metabolic rate. However, Levine et al. (20) have shown that this effect disappears after only 4 d of abstinence. Because all measurements were performed at least 5 d after admission and we have confirmed our findings in two assessments of EE done on separate days, it seems unlikely that alcohol use or previous overeating would have affected the EE measurements. Furthermore, we found that RMR but not SLEEP predicted mortality. Because SLEEP is a measurement carved from the 24EE based on a defined time period and low activity, it may have more variability and less accuracy compared with RMR, accounting for our lack of an association with mortality. Individual EE measurements can vary from day to day. However, under the conditions on our unit, the reproducibility of our measurements is high with an intra-individual coefficient of variation of approximately 2% (6).
Two different measurements of EE (24EE and RMR) measured on different days predict natural mortality in Pima Indians, supporting a role for increased energy turnover as a risk factor for accelerated aging and early mortality.
Adenosine-5'-triphosphate (ATP) is a multifunctional nucleotide used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism. It is produced by photophosphorylation and cellular respiration and used by enzymes and structural proteins in many cellular processes, including biosynthetic reactions, motility, and cell division. One molecule of ATP contains three phosphate groups, and it is produced by ATP synthase from inorganic phosphate and adenosine diphosphate (ADP) or adenosine monophosphate (AMP).
Metabolic processes that use ATP as an energy source convert it back into its precursors. ATP is therefore continuously recycled in organisms: the human body, which on average contains only 250 grams (8.8 oz) of ATP, turns over its own body weight in ATP each day.
ATP is used as a substrate in signal transduction pathways by kinases that phosphorylate proteins and lipids, as well as by adenylate cyclase, which uses ATP to produce the second messenger molecule cyclic AMP. The ratio between ATP and AMP is used as a way for a cell to sense how much energy is available and control the metabolic pathways that produce and consume ATP. Apart from its roles in energy metabolism and signaling, ATP is also incorporated into nucleic acids by polymerases in the processes of DNA replication and transcription.
The structure of this molecule consists of a purine base (adenine) attached to the 1' carbon atom of a pentose sugar (ribose). Three phosphate groups are attached at the 5' carbon atom of the pentose sugar. It is the addition and removal of these phosphate groups that inter-convert ATP, ADP and AMP. When ATP is used in DNA synthesis, the ribose sugar is first converted to deoxyribose by ribonucleotide reductase.
ATP was discovered in 1929 by Karl Lohmann, but its correct structure was not determined until some years later. It was proposed to be the main energy-transfer molecule in the cell by Fritz Albert Lipmann in 1941. It was first artificially synthesized by Alexander Todd in 1948.