Calorie Restriction and Metabolic Health in Older Adults

Bettina Mittendorfer, Ph.D. 


Project Overview:
Calorie restriction (CR) in overweight and obese subjects has many benefits; it increases insulin sensitivity, and reduces cardiovascular (CVD) risk. Therefore, CR is the cornerstone of treatment to improve health in obese persons. CR also increases maximal lifespan in a variety of non-human species, so it is being promoted as a means to potentially increase lifespans in lean adults.

The effect of CR on health in lean human subjects is not clear. In healthy, lean individuals, CR could potentially be harmful because it is known to decrease muscle mass, bone mass and bone mineral density. This has minimal clinical implications in obese persons, because they have greater muscle mass and bone mineral density than lean people, and obese subjects lose less body protein during negative energy balance than do lean subjects. But in lean individuals, CR could cause sarcopenia, osteopenia/osteoporosis and impair physical function, which are predictors of frailty and disability and premature death, because of their relatively small baseline muscle and bone mass and bone mineral density.

This study will evaluate the effect of calorie restriction in lean older adults on metabolism, muscle and bone, and will test if additional protein intake can prevent the potential harmful effects of calorie restriction in lean subjects.


Final Report Abstract:
Calorie restriction (CR) in obese subjects has many benefits; it increases insulin sensitivity, and reduces cardiovascular risk.  Therefore, CR is the cornerstone of treatment to improve health in obese persons.  In addition, it is being promoted to potentially increase lifespan in non-obese adults because CR increases maximal lifespan in a variety of non-human species.  The effect of CR on health in non-obese human subjects is not clear.  In fact, CR in healthy, non-obese individuals could potentially be harmful because it decreases muscle mass, bone mass and bone mineral density.  This has minimal clinical implications in obese persons, because they have greater muscle mass and bone mineral density than lean people, and obese subjects lose less body protein during negative energy balance than do lean subjects.  However, CR in non-obese individuals could cause sarcopenia, osteopenia/osteoporosis and impair physical function, which are predictors of frailty and disability and premature death, because of the relatively small baseline muscle and bone mass and bone mineral density.  In addition, we have recently found that a group of lean men and women who have undergone self-imposed CR for years based on the belief that CR will extend their lifespan not only have low muscle mass and bone mass and bone mineral density but also have impaired oral glucose tolerance.  CR in non-obese subjects could therefore have detrimental health consequences, but this issue has not been carefully studied in prospective, randomized controlled trials.  Accordingly, the overall purpose of this proposal was to provide a comprehensive evaluation of the effects of CR on metabolic health in healthy, non-obese, older adults.  We found that CR in non-obese subjects leads to muscle loss and does not have the same beneficial effects as in obese subjects who experience significant improvements in insulin sensitivity after similar amount of weight loss.  These results contrast those from non-obese non-human species (e.g., rodents, fish, flies, worms, and monkeys) in which CR delayed the onset of metabolic disease, prevented the age-associated loss of muscle mass, and increased both average and maximal life span.

Lay Summary:
Calorie restriction (reduced food intake) has many health benefits in obese subjects.  Calorie restriction has also been proposed to be beneficial in lean persons, because it was found to delay the onset of disease and prolong life in many animal species.  The effect of calorie restriction on health in non-obese persons, however, is not clear and it is possible that it may even be harmful.  We evaluated the effect of calorie restriction in non-obese persons and found that it leads to muscle loss and does not improve metabolic health.

Introduction:
Calorie restriction (CR) in obese subjects has many benefits; it increases insulin sensitivity, and reduces cardiovascular risk.  Therefore, CR is the cornerstone of treatment to improve health in obese persons.  In addition, it is being promoted to potentially increase lifespan in non-obese adults because CR increases maximal lifespan in a variety of non-human species.  The effect of CR on health in non-obese human subjects is not clear.  In fact, CR in healthy, non-obese individuals could potentially be harmful because it decreases muscle mass, bone mass and bone mineral density.  This has minimal clinical implications in obese persons, because they have greater muscle mass and bone mineral density than lean people, and obese subjects lose less body protein during negative energy balance than do lean subjects.  However, CR in non-obese individuals could cause sarcopenia, osteopenia/osteoporosis and impair physical function, which are predictors of frailty and disability and premature death, because of the relatively small baseline muscle and bone mass and bone mineral density.  In addition, we have recently found that a group of lean men and women who have undergone self-imposed CR for years based on the belief that CR will extend their lifespan not only have low muscle mass and bone mass and bone mineral density but also have impaired oral glucose tolerance.  CR in non-obese subjects could therefore have detrimental health consequences, but this issue has not been carefully studied in prospective, randomized controlled trials.  Accordingly, the overall purpose of this proposal was to provide a comprehensive evaluation of the effects of CR on metabolic health in healthy, non-obese, older adults.

Methods and Results:
We evaluated basal (overnight fasted) plasma lipid, glucose and insulin concentrations, and insulin-mediated suppression of hepatic glucose production (glucose rate of appearance in plasma) and glucose disposal (glucose rate of disappearance form plasma) by using the hyperinsulinemic-euglycemic clamp technique in conjunction with [6,6-2H2]glucose infusion.  We studied 14 non-obese 58 ± 5 year old women before and after CR therapy which induced a 7.5 ± 0.7 % (mean ± SEM) weight loss, which was comprised of a ~10 % reduction in fat mass and a ~5 % reduction of fat-free mass, which is mostly muscle (Table 2).  CR also reduced intrahepatic triglyceride content but had no effect on visceral adipose tissue volume, plasma lipid, insulin and glucose concentrations and glucose kinetics during basal conditions and the hyperinsulinemic clamp (Table 2).

 

Before

After

Body mass index (kg/m2)

25 ± 1

23 ± 1

Body weight (kg)

69 ± 3

63 ± 2*

Fat mass (kg)

29 ± 1

26 ± 1*

Fat-free mass (kg)

42 ± 1

40 ± 1*

Intrahepatic triglyceride (%)

3.4 ± 0.8

1.8 ± 0.4*

Visceral adipose tissue (cm3)

1057 ± 139

930 ± 131

Plasma triglyceride (mg/dl)

94 ± 8

89 ±

LDL-cholesterol (mg/dl)

119 ± 7

113 ± 7

HDL-cholesterol (mg/dl)

56 ± 4

53 ± 3

Insulin (U/l)

5.8 ± 1.1

4.1 ± 0.6

Glucose (mg/dl)

91 ± 2

89 ± 2

Glucose Ra (μmol/kg FFM/min)

 

 

Basal

16.2 ± 0.7

16.3 ± 0.5

Clamp

4.2 ± 0.6

3.9 ± 0.6

Glucose Rd (μmol/kg FFM/min)

 

 

Basal

16.5 ± 0.7

16.7 ± 0.5

Clamp

79 ± 4

73 ± 3

Ra: rate of appearance; Rd: rate of disappearance.  * value significantly different
from value before weight loss; p<0.05.

Discussion, including implications and potential long-term extensions:
The results from these studies suggest that CR in non-obese subjects leads to muscle loss and does not have the same beneficial effects as in obese subjects who experience significant improvements in insulin sensitivity after similar amount of weight loss1.  These results contrast those from non-obese non-human species (e.g., rodents, fish, flies, worms, and monkeys) in which CR delayed the onset of metabolic disease, prevented the age-associated loss of muscle mass, and increased both average and maximal life span2-5.

Future plans including planned grant submissions:
We have obtained funding from the NIH (R01) to study the effect of calorie restriction with and without protein supplementation on metabolic health in older adults.  We hypothesize that increased dietary protein intake can ameliorate the adverse effects of CR on the musculoskeletal system because of the beneficial effect of protein on muscle and bone metabolism.

Literature cited:
1.    Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 2009;136:1552-60.
2.    Fontana L, Klein S. Aging, adiposity, and calorie restriction. Jama 2007;297:986-94.
3.    Holloszy JO. Mortality rate and longevity of food-restricted exercising male rats: a reevaluation. J Appl Physiol 1997;82:399-403.
4.    Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science (New York, NY 2009;325:201-4.
5.    Colman RJ, Beasley TM, Allison DB, Weindruch R. Attenuation of sarcopenia by dietary restriction in rhesus monkeys. J Gerontol A Biol Sci Med Sci 2008;63:556-9.