Search

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neural development is controlled at multiple levels to orchestrate appropriate choices of cell fate and differentiation. Although more attention has been paid to the roles of neural-restricted factors, broadly expressed factors can have compelling impacts on tissue-specific development. Here, we describe in vivo conditional knockout analyses of murine Ars2, which has mostly been studied as a general RNA-processing factor in yeast and cultured cells. Ars2 protein expression is regulated during neural lineage progression, and is required for embryonic neural stem cell (NSC) proliferation. In addition, Ars2 null NSCs can still transition into post-mitotic neurons, but fail to undergo terminal differentiation. Similarly, adult-specific deletion of Ars2 compromises hippocampal neurogenesis and results in specific behavioral defects. To broaden evidence for Ars2 as a chromatin regulator in neural development, we generated Ars2 ChIP-seq data. Notably, Ars2 preferentially occupies DNA enhancers in NSCs, where it colocalizes broadly with NSC regulator SOX2. Ars2 association with chromatin is markedly reduced following NSC differentiation. Altogether, Ars2 is an essential neural regulator that interacts dynamically with DNA and controls neural lineage development., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Objective: We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women., Research Design and Methods: We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 +/- 4 years, n = 88; group 2, 46 +/- 2 years, n = 38; group 3, 53 +/- 2 years, n = 31; and group 4. 67 +/- 6 years, n = 21., Results: Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, age-related changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on age-related changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted., Conclusions: We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue.

Adiposity increases with age. The size of the adipose tissue mass is determined by the balance between the recruitment of lipid substrates (ie free fatty acids) from adipose tissue and their subsequent oxidation by respiring tissues. Thus, change in the liberation of free fatty acids from adipocytes, the capacity of respiring tissue to oxidize free fatty acids or a combination of both may contribute to the age-related increase in body fat. This review focuses on studies that have examined the effect of age on free fatty acid release and the capacity of respiring tissues to oxidize fat. In vitro studies have shown that hormonal and pharmacological stimulation of lipolysis diminished with age. Despite this cellular defect, however, in vivo studies suggest that fatty acids are recruited from adipose tissue in excess of the energy demands of the body in older individuals. The capacity of respiring tissues, in particular skeletal muscle, to oxidize fat declines with age. The age-related decrease in fat oxidation is related to a reduction in both the quantity and oxidative capacity of respiring tissue. Taken together, these results suggest that an age-related decrease in the capacity of respiring tissues to oxidize fat, rather than decreased free fatty acid release, is a more likely determinant of lipid imbalance and the age-related increase in adiposity. Interventions designed to increase the mass or oxidative capacity of respiring tissue, therefore, may be effective in counteracting the age-related reduction in fat oxidation.

Purpose: The purpose was to review studies that have examined the effect of aerobic (AEX) or resistance exercise (REX) on body composition in older individuals (>55 yr). Our goal was to examine the effect of these two exercise paradigms on fat mass and fat-free mass and to consider those factors that may explain variability in findings among studies., Methods: We conducted a literature search (Medline, 1984-1999) for intervention studies (at least 2 months in duration) that have examined the independent effect of either REX or AEX on body composition in older individuals., Results: AEX decreased fat mass (range: -0.4 to -3.2 kg) but had little effect on fat-free mass. The change in fat mass with AEX was related to the duration of the exercise program (r = 0.51; P < 0.02) but not to body composition methodology. In contrast, REX reduced fat mass (range: -0.9 to -2.7 kg) and increased fat-free mass (range: 1.1 to 2.1 kg). Changes in body composition with REX were not related to body composition methodology or the duration of the exercise program., Conclusion: Both AEX and REX appear to be beneficial in reducing body fat. REX appears to have the additional benefit of increasing fat-free mass.

Misreporting of total energy intake occurs frequently in dietary studies. Relatively few studies have been performed in older individuals who may be vulnerable to obesity and its associated health risks. In the present study, we examined misreporting of total energy intake by comparing self-reported food intake, measured by 3-day food diaries, to energy expenditure, measured with the doubly labeled water technique, in a relatively large sample of older men (n = 39) and women (n = 43). An additional objective was to identify potential predictors of misreporting, including body composition, fitness as assessed by peak VO2, and sociodemographic characteristics such as gender, living arrangement, education, and income. In general, men and women underreported total energy intake. The magnitude of the underreporting, as measured by percent difference between reported intake and measured total energy expenditure, was comparable between the sexes. Body mass index, waist circumference, and fat mass were significant correlates of underreporting of total energy intake, with heavier individuals underreporting more than leaner individuals. Among the demographic variables, living arrangement was a significant determinant of misreporting of total energy intake in older people. Individuals in marriage-like living arrangements underreported their total energy intake to a greater extent than married individuals. However, the magnitude of misreporting by those living alone did not differ from that of married individuals. The results of the present study highlight the need to examine misreporting of total energy intake in older individuals, who are more prone to obesity and its health risks.

We examined daily energy requirements and determinants of physical activity in older, free-living African-American women (n = 37; age, 64 +/- 8 yr) and men (n = 28; age, 64 +/- 7 yr). Total daily energy expenditure and its components [i.e. resting metabolic rate (RMR) and physical activity energy expenditure] were determined using doubly labeled water and indirect calorimetry. Body composition from dual energy x-ray absorptiometry, maximal oxygen consumption from a graded treadmill test, and leisure time physical activity from a structured interview were determined. Total daily energy expenditure adjusted for body composition was lower (P < 0.05) for women (2198 +/- 621 kcal/d) than for men (2633 +/- 669 kcal/d) due to a lower RMR (1431 +/- 240 vs. 1576 +/- 259 kcal/d; P = 0.07) and physical activity energy expenditure (548 +/- 559 vs. 794 +/- 603 kcal/d; P = 0.19), respectively. The physical activity level ratio (i.e. total daily energy expenditure/RMR) was not different from Food and Agriculture Organization/World Health Organization/United Nations University recommendations (i.e. 1.51) for women (1.51 +/- 0.25), but was higher for men (1.71 +/- 0.32). The strongest correlates with physical activity energy expenditure were age for women (r = -0.44; P < 0.01) and maximal oxygen consumption for men (r = 0.39; P < 0.05). These data show that daily energy requirements are significantly lower in African-American women compared to men, primarily due to lower levels of physical activity energy expenditure. Furthermore, lower levels of cardiovascular fitness in men and advancing age in women are associated with lower physical activity energy expenditure.

We determined the contribution of body fat distribution, peak VO2, fat mass, and dietary intake to variation in plasma lipids in elderly individuals. Volunteers were a healthy cohort of older Caucasian women (n = 75, mean age +/- SD, 72 +/- 5 years) and older men (n = 101, 72 +/- 5 years). We determined fat mass from underwater weighing, fat patterning from waist circumference, as well as peripheral and truncal skinfolds, exercise capacity from peak VO2, and dietary intake from three-day food diaries. Plasma lipid levels were measured in the fasting state and included total cholesterol, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), and fasting triglycerides. Older women weighted less than older men, but had higher fat mass, truncal, and peripheral skinfolds. Waist circumference and peak VO2 were lower in older women than older men. Older women had higher total cholesterol (217 +/- 31 vs. 197 +/- 30; p < 0.01), HDL-C (54 +/- 12 vs. 49 +/- 14; p < 0.05), and LDL-C (133 +/- 26 vs. 121 +/- 27; p < 0.01) when compared with older men. No gender differences were noted in fasting triglycerides. Truncal skinfolds were the best predictor of plasma lipids in older men, accounting for between 9% and 30% (r2) of the variation in plasma lipids. Similarly, in older women, central markers of fatness (i.e., waist circumference and truncal skinfolds) were the best predictors of plasma lipids (r2 = 3% to 24%). Total fat mass, peak VO2 and dietary intake were not independent predictors of plasma lipids in older men and women. Indices of central body fatness, rather than total fat mass, peak VO2 or dietary intake are stronger predictors of plasma lipids in healthy older men and women.

The physiological factors mediating gender differences in resting metabolic rate (RMR) in older individuals are presently unclear. We examined the contribution of sympathetic nervous system activity to gender differences in resting metabolic rate in older men and women and its relation to body fat distribution. We performed measurements of noradrenaline (NA) kinetics from infusions of [3H]-NA, RMR, body fat distribution, body composition, peak Vo2 and dietary intake in 29 older men (69 +/- 6 years) and 26 older women (65 +/- 5 years). Older men weighed more (P < 0.01) and had a greater fat-free mass (P < 0.01) and a larger waist circumference (P < 0.01) than older women. Older men had a higher RMR (P < 0.05) than older women, which persisted after controlling for differences in fat-free mass and fat mass. Older men also showed a greater NA appearance rate (P < 0.01) at rest than older women. The higher NA appearance rate in older men was partly related to their greater waist circumference (r = 0.50, P < 0.01). We explored the sympathetic contribution to gender differences in RMR by statistically controlling for differences in body composition and NA appearance rate. After this procedure, we found no gender differences in adjusted RMR between older men (4.3 +/- 0.5 kJ min(-1)) and older women (4.3 +/- 0.4 kJ min(-1)). Our results suggest that: (a) older men have a higher RMR than older women independent of differences in body composition; (b) the higher RMR in older men may be partly due to higher levels of sympathetic nervous system activity; (c) the higher sympathetic nervous system activity in older men is partly related to their greater waist circumference, a proxy measure of central body fatness.

The independent and collective influences of several physiological factors on the age-related increase in blood pressure in healthy men were examined. Twenty-seven younger and 25 older, mostly normotensive, healthy men were studied. Blood pressure, body fat, body fat distribution, maximal oxygen consumption (VO2max), plasma norepinephrine, dietary Na, and erythrocyte Na-K pump activity were measured. Older men showed 57% higher percent body fat, 40% higher plasma norepinephrine concentration, 14% greater mean arterial blood pressure (MAP), and 5% higher plasma K concentration than younger men (all p < 0.01). Older men showed a 38% (p < 0.01) lower VO2max, 19% (p < 0.05) lower energy intake, 18% (p < 0.05) lower Na-K pump rate constant, and a 17% (p < 0.05) lower Na-K pump rate. Group means for MAP were adjusted for combinations of plasma norepinephrine, waist:thigh ratio, VO2max, and the Na-K pump rate constant, to determine if any one variable or combination could account for the age related increase in MAP. Statistical adjustment for plasma norepinephrine, waist:thigh ratio, and Na-K pump rate constant eliminated the significant difference between MAPs for the two groups. Thus, alterations in sympathetic nervous system activity, body fat distribution, and the membrane Na-K pump activity independently contribute to the age-related increase in MAP in healthy men.

Alterations in the mobilization and oxidation of fat may partially account for age-related alterations in body composition. To investigate age-related alterations in fat metabolism, we compared basal rate of appearance of free fatty acids (FFAapp) and total body fat oxidation as measured by infusions of [14C] palmitate and indirect calorimetry, respectively, in 18 younger (23 +/- 1 yr) and 30 older (69 +/- 1 yr) men. We also examined whether age-related differences in body composition, body fat distribution, peak oxygen consumption, dietary intake, and/or fasting insulin levels may explain age-related variation in FFAapp and total body fat oxidation. The FFAapp showed a tendency to be higher in older compared with younger men (1,134 +/- 184 vs. 680 +/- 105 mu mol/min; P = 0.07), whereas total body fat oxidation was similar between groups (257 +/- 25 vs. 222 +/- 9 mu mol/min). The estimated rate of nonoxidative disposal of free fatty acids showed a tendency to be higher in the older (913 +/- 182 mu mol/min) than in younger men (423 +/- 103 mu mol/min; P = 0.06). Fat-free mass was the most significant predictor of FFAapp in younger (r = 0.63; P < 0.01) and older (r = 0.41; P < 0.05) men. These results suggest that older men recruit fatty acids from adipose tissue stores in excess of the energy needs of respiring tissue. However, variation in FFAapp between the age groups could not be explained by differences in body habitus or fasting insulin levels.

Background: Increasing levels of total and central body fat with advancing age contribute to the development of cardiovascular and metabolic disease. We examined gender-related differences and physiological predictors of the rate of increase in total and central body fat in men and women., Methods: We studied 427 healthy men (age range, 17 to 90 years) and 293 women (age range, 18 to 88 years). We measured body fatness by hydrostatic weighing, central adiposity from the waist circumference, peak volume of oxygen utilization (VO2) from a treadmill test, leisure time physical activity (LTA) from a questionnaire, resting metabolic rate and respiratory quotient from indirect calorimetry, and energy intake from 3-day food diaries., Results: Fat mass increased with age, and the rate was greater in women (r = .61; slope = 0.25 kg/y; P < .01) than in men (r = .43; slope = 0.16 kg/y; P < .01). Increasing fat mass in men and women was most strongly associated with declines in peak VO2 and LTA. Controlling for these variables reduced the increase in fat mass from 17% to 3% per decade in men and from 26% to 5% per decade in women. The increase in waist circumference with age was also greater in women (r = .53; slope = 0.28 cm/y) than in men (r = .39; slope = 0.18 cm/y; P < .01). Increasing waist circumference with age in men and women was most strongly associated with declines in LTA and peak VO2, respectively. Control for these variables reduced the age-related increase in waist circumference from 2% to 1% per decade in men and from 4% to 1% per decade in women. We observed no independent contribution of resting metabolic rate, respiratory quotient, menopause status, energy, or macronutrient intake to the age-related increase in fat mass and waist circumference., Conclusions: Our findings suggest that (1) the age-related increase in fat mass and waist circumference is greater in women than in men and (2) the physiological characteristics that reflect a decline in physical activity-related energy expenditure, rather than resting energy expenditure, are important predictors of the increases in total and central fatness. Lifestyle changes that increase the level of physical activity may be advantageous in blunting age-related increases in total and central body fatness.

Objective: Elevated levels of fasting insulin increase the risk for coronary artery disease. In this study, we considered the independent contributions of age, total body fatness, abdominal fat distribution, peak aerobic capacity, leisure time physical activity, dietary intake, and fasting glucose levels to the age-associated increase in fasting insulin levels in healthy men and women., Design: A cross-sectional analysis., Subjects: A total of 427 healthy men and 293 healthy women age 18 to 90 years., Measurements: Plasma glucose and insulin levels were measured in the fasted state and subjects were characterized for body fatness from underwater weighting, abdominal fat distribution from the waist circumference, peak VO2 from a treadmill test to exhaustion, leisure time physical activity from a structured interview and dietary intake from a 3-day food diary. The independent predictors of fasting insulin levels were determined by stepwise multiple regression analysis., Results: Fasting insulin concentrations increased with age in both men (0.09 +/- 0.02 pmol/yr, unadjusted slope +/- SEE) and women (0.14 +/- 0.03 pmol/yr). In men, the major independent predictors of fasting insulin levels were percent body fat (r2 = 28%, P < 0.001) and waist circumference (r2 = 3% P < 0.001). Age, glucose concentration, and peak VO2 were small (1% each), but independent contributors to the variance in insulin levels. In women, the waist circumference (r2 = 18%, P < 0.001) and the fasting glucose concentration (r2 = 7%, P < 0.001) were the independent correlates of fasting insulin concentrations., Conclusions: Our data suggest that total adiposity and central body fat distribution are significant determinants of the increase in fasting insulin levels, whereas age, dietary intake, and levels of aerobic fitness and physical activity appear to be less important contributors to the variation in fasting insulin concentrations in healthy men and women.

We examine the association of the menopause transition, congestive heart failure, and Parkinson's disease on body composition and energy expenditure. We present evidence suggesting that the normal menopausal transition is associated with accelerated loss of fat-free mass, a decline in resting metabolic rate, and increased central body fatness. Second, we show that the cardiac cachexia associated with heart failure is partially due to an elevated level of energy expenditure. Despite having a lower quantity of fat-free mass, congestive heart failure patients have a higher resting metabolic rate (approximately 283 kcal/d) for their metabolic size than healthy elderly. The elevated level of resting energy expenditure probably contributes to their unexplained weight loss. Parkinson's patients experience muscular rigidity and tremor which could contribute to inappropriately high levels of energy expenditure and difficulty in maintaining body weight and composition. We examined resting metabolic rate and body composition in eight Parkinson's patients and 34 healthy age-matched controls. Parkinson's patients showed lower levels of fat-free mass (approximately 6 kg), but similar resting metabolic rates (1601 +/- 250 kcal/d) versus healthy controls (1671 +/- 212 kcal/d), suggesting a hypermetabolic state. A re-examination of daily energy needs and the metabolic factors contributing to periods of energy imbalance during the menopausal transition and in several disease states may be a prerequisite to offsetting accelerated sarcopenia.

It was hypothesized that an increase in total and central body fatness is related to higher sympathetic nervous system activity (SNSA) in older men. Resting SNSA was measured from norepinephrine (NE) kinetics in 69 younger (18-36 yr) and 69 healthy older men (55-80 yr). Body fat distribution was estimated from the waist circumference, body composition from underwater weighing, peak oxygen consumption from a treadmill test to exhaustion, and dietary intake from food diaries. Plasma NE concentrations were 41% higher (P < 0.001) in older men due to a 27% increase (P < 0.001) in NE appearance rate and a tendency for a lower NE clearance rate (P = 0.08). NE appearance rate was higher in individuals of both age groups who exhibited a greater waist circumference and body fatness (range of r values 0.49-0.69; P < 0.01). The waist circumference, and not age, was the strongest predictor of the increase in NE appearance rate in older men. Statistically controlling for the waist circumference or body fatness diminished age-related differences in NE concentrations and in NE appearance rate. These findings suggest that an accumulation of total and central body fat is associated with higher levels of SNSA in older males.

Resting metabolic rate (RMR) data have been normalized by dividing RMR by fat-free mass (FFM) (ie, ratio method), or by using a regression-based approach. We compared both data-normalization procedures on age- and sex-related differences in RMR. The ratio method showed no differences in adjusted RMR between older men (0.084 +/- 0.004 kJ.FFM-1.min-1) and younger men (0.082 +/- 0.003 kJ.FFM-1.min-1), whereas analysis of covariance showed a lower (P < 0.01) adjusted RMR in older men (4.81 +/- 0.04 kJ/min) than in younger men (5.14 +/- 0.04 kJ/min). In another example, the ratio method showed that women had a higher (P < 0.05) adjusted RMR (0.10 +/- 0.004 kJ/min) than did men (0.08 +/- 0.003 kJ/min), whereas analysis of covariance showed a lower (P < 0.01) adjusted RMR in women (4.45 +/- 0.03 kJ/min) than in men (4.62 +/- 0.03 kJ/min). The ratio method provides misleading conclusions regarding sex- and age-related differences in RMR when compared with a regression-based approach.

We examined the contribution of variations in body composition and leisure time physical activity to the age-related decline in peak oxygen consumption (VO2) in men and women. Healthy males 17-80 yr old (n = 378) and females 18-81 yr old (n = 224) were characterized for peak VO2 from a treadmill test to exhaustion, fat-free mass and fat mass by underwater weighing, and leisure time physical activity. Peak VO2 showed a greater absolute decline (P < 0.05) with age in males (r = -0.70, slope = -0.034 l.min-1.yr-1; P < 0.01) than in females (r = -0.78, slope = -0.028 l.min-1.yr-1; P < 0.01). After statistically controlling for differences in fat-free mass and fat mass, the decline in peak VO2 was diminished in both sexes, although a greater rate of decline persisted in males (r = -0.47, slope = -0.016 l.min-1.yr-1; P < 0.01) than in females (r = -0.39, slope = -0.009 l.min-1.yr-1; P < 0.01). We found that the addition of leisure time physical activity (independent of body composition) to the regression model further attenuated the rate of decline in males (r = -0.40, slope = -0.013 l.min-1.yr-1; P < 0.01) but did not alter the age-related decline in peak VO2 in females (r = -0.39, slope = -0.009 l.min-1.yr-1; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the hypothesis that a decline in Na-K pump activity contributes to the lower resting metabolic rate (RMR) in older males, independent of the loss of fat-free mass. Plasma and erythrocyte Na and K concentrations were measured using flame photometry. Changes in these concentrations after incubation with and without ouabain were used to calculate erythrocyte Na-K pump rate and rate constant in 27 younger (28 +/- 7 yr) and 25 older (67 +/- 6 yr) men. Older men showed an 18% lower erythrocyte Na-K pump rate constant (0.32 +/- 0.09 vs. 0.39 +/- 0.10 h-1; P < 0.01), a 12% lower RMR (1.10 +/- 0.14 vs. 1.25 +/- 0.14 kcal/min; P < 0.01) and an 8% lower level of fat-free mass (61.7 +/- 5.8 vs. 67.4 +/- 8.1 kg; P < 0.01) relative to younger men. A lower RMR persisted in older men (1.14 +/- 0.12 kcal/min) compared to younger men (1.21 +/- 0.12 kcal/min; P < 0.05) after control for the effect of fat-free mass. No differences in RMR were found, however, between older (1.17 +/- 0.13 kcal/min) and younger men (1.20 +/- 0.13 kcal/min) after controlling for both fat-free mass and the erythrocyte Na-K pump rate constant. A positive relation was noted between RMR and the erythrocyte Na-K pump rate constant, after removing the effects of fat-free mass (partial r = 0.30; P < 0.05). Our results support the conclusions that: 1) the in vivo activity of the Na-K pump is related to RMR, and 2) the age-related reduction in Na-K pump activity is a partial contributor to the decline in RMR in older men.

We considered the association of several metabolic and lifestyle variables as modulators of the decline in resting metabolic rate (RMR) and fat-free weight (FFW) in 183 healthy females (18-81 yr). RMR showed a curvilinear decline with age, which was significant in women aged 51-81 yr but not in women aged 18-50 yr. FFW showed a curvilinear decline with age, which was significant (P < 0.01) in women 48-81 yr but not in women 18-47 yr. The decline in RMR was primarily associated with the loss of FFW (r2 = 72%), whereas the decline in FFW was explained primarily by differences in maximal O2 consumption (VO2max), age, leisure time physical activity, and dietary protein intake (total r2 = 46%). We conclude that RMR and FFW showed a curvilinear decline with age which was accelerated beyond the middle-age years. Second, the age-related decline in RMR was primarily associated with the loss of FFW. Third, the loss of FFW was partially related to a decrement in VO2max and nutritional factors. Therapeutic interventions designed to increase VO2max by elevating physical activity may preserve fat-free weight and thus offset the decline of RMR in aging women.