Human vs. nonhuman primate CR affects uncertain?

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The original comment had been commented upon by the pdf-available:

Lane MA, Mattison JA, Roth GS, Brant LJ, Ingram DK.

Effects of long-term diet restriction on aging and longevity in primates remain

uncertain.

J Gerontol A Biol Sci Med Sci. 2004 May;59(5):405-7. No abstract available.

PMID: 15123747

, in the last of the

references in the below list.

The below is the response to that report.

Bodkin NL, Ortmeyer HK, Hansen BC.

A comment on the comment: relevance of nonhuman primate dietary restriction to

aging

in humans.

J Gerontol A Biol Sci Med Sci. 2005 Aug;60(8):951-2. No abstract available.

PMID: 16127095

IN rodents and many other species, dietary restriction (DR), also known as

calorie

restriction, has been shown to prevent and/or delay the onset of many

age-related

diseases, and maintain healthy physiological function during the aging process.

Although Lane and colleagues agree that our published report (1) provides a

preliminary interesting assessment of the relevance of DR to human aging, they

have

also raised issues which we would like to address.

Dr. Lane and his colleagues have suggested that our study should have used

" controls

typically used in rodent DR studies. " However, our study was initiated after

more

than 10 years of study in feeding regulation, body weight, and obesity in

monkeys.

Therefore we had a strong knowledge base from both research and experience that

the

" rodent " approach would not be appropriate to maintaining healthy DR in monkeys.

Primates (both nonhuman and human) have a wide range of calorie requirements,

and

even at the same lean body mass, individuals differ substantially in energy

expenditure. Thus, an approach to DR that does not take into account these

individual differences is destined for failure.

We agree that there are very important questions to be raised about the " control

group " (in this case, the ad libitum-fed monkeys) including the following: 1)

What

diet and nutritional constraints should be placed on the control group? (We

chose

fully ad libitum feeding conditions. Lane and colleagues indicate in prior

publications that they have chosen to compare two groups of monkeys, both of

which

are calorie restricted; one, however, is more restricted than the other.) 2)

Shall

the control group be expected to have a significant incidence of overweight and

obesity similar to 60%–70% of the U.S. population, particularly in middle-aged

humans, who also have ad libitum food availability? (We believe the answer is

yes,

and therefore permitted individual monkey body weights in the ad libitum-fed

group

to develop without constraint and without dietary manipulation.) 3) Shall a

large

proportion of the control group be expected to develop type 2 diabetes? (We

believe

the answer is yes—allow the control group to progress naturally with regard to

aging

and aging-related diseases). Thus, we acknowledge that the issues with the

" control "

group are obviously much more complex than the simple question of number of

animals

per group.

Although the study design may appear incongruent to some gerontologists, in

fact,

the large number of control animals and fully ad libitum feeding allowed the

control

group to emerge (as in humans) into the full range of metabolic

possibilities—from

lean metabolically normal aged monkeys to monkeys of all ages with various

degrees

of adiposity, prediabetes, and overt type 2 diabetes. We believe that the

optimal

control group must be many-fold larger than the DR group (in this case the ratio

of

ad libitum-fed monkeys to DR monkeys was approximately 15:1) because of the

diversity of metabolic outcomes that can be expected with ad libitum feeding. In

contrast, DR produces substantially greater homogeneity with regard to metabolic

outcomes.

Dr. Lane and his colleagues appear to be seeking differences in the ad

libitum-fed

primates versus the DR primates, prior to the monkey's entry to the Obesity and

Diabetes Research Center (ODRC). However, all monkeys were screened before entry

to

the ODRC; this screening included gathering background information from the

attending veterinarian at the originating facility and reviewing the medical

records

of the monkey. All monkeys were research naïve and tuberculosis negative and had

a

normal chemistry/hematology profile (indicating normal electrolyte, liver, and

kidney function) and normal laboratory behavioral characteristics. Therefore,

the ad

libitum-fed and DR monkeys differed little, if at all, with regard to health

parameters and history.

As stated, all monkeys were individually housed and maintained under identical

laboratory conditions (including light cycling, temperature, and humidity) over

the

duration of the study, and decisions concerning treatment of disease and

euthanasia

were consistently made by the same principal investigator in consultation with

the

clinical veterinarian. Therefore, procedural and methodological variables were

very

well controlled. Concerning questions about the diet, the monkeys were

maintained on

standard primate chow. Only 16 of 109 monkeys received Ensure, and it was used

only

briefly to obtain exact calorie intakes. The Ensure diet contained 31% fat,

which

cannot be considered " high fat, " particularly when used for only a brief period

in

the entire life of the primate. We determined and reported that the ad libitum

calorie intake did not differ for individual monkeys between the two diets (2).

Food intake by all monkeys was determined a minimum of twice daily throughout

this

study. As described, we adjusted the calorie intake of each DR monkey on a

weekly

basis to maintain stable adult body weight (this is similar in humans to a

" bathroom

scale " method of feedback). There was no significant weight gain or loss in the

DR

group, as food intake was titrated to maintain a lean healthy body weight. In

contrast, ad libitum-fed monkeys always had food available, much like many

humans

today. Many, but not all, of the ad libitum-fed monkeys gained weight over the

years

(as also happens to ad libitum-fed humans in middle age).

The comments by Lane and colleagues concerning the body weights and body fat of

ad

libitum-fed adult rhesus monkeys were not correct. Our adult monkeys have ranged

in

body weight from 8 kg to 31 kg. The individual body weight of each ad

libitum-fed

monkey was self-determined; therefore, the ad libitum-fed monkeys provide the

fully

relevant group for comparison to the weight-stabilized calorie-titrated DR

group.

The prior commentary (10) also expressed concern about the differences between

the

ad libitum-fed and the DR groups, specifically with regard to adiposity and

insulin

levels. As noted in the published paper: " All the monkeys were metabolically

well-characterized, including age, weight, fasting plasma insulin, fasting

plasma

glucose, glucose tolerance, acute insulin response, and insulin sensitivity. We

sought to determine if there were differences in the survival of the two groups

of

monkeys based on AL vs. DR conditions, and to identify the major morbidity and

causes of death in each group, including associations with metabolic factors.

The

metabolic differences between the subgroups of AL monkeys allowed the

statistical

testing of each subgroup vs. the DR group ... " (1). Furthermore, the additional

comparisons were requested by one of the original reviewers of the manuscript,

and

we followed that suggestion to include the various metabolically defined

subgroups

in Table 1 of our article.

By analysis of subgroups (e.g., those with hyperinsulinemia), we determined and

reported that " ... the risk of death for a hyperinsulinemic monkey was 3.7 times

higher (p <.05) as compared with a DR monkey of the same age. Comparison of the

AL-fed monkeys and the DR monkeys, after adjusting for baseline body weight,

fasting

plasma insulin, fasting plasma glucose, and peripheral insulin sensitivity (M),

showed that the risk of death was decreased by 7% per unit increase in insulin

sensitivity ... " (1). DR has been shown to lead to improved glucose utilization

in

rodents (3) and in primates (4–9). Indeed, as our studies and those of many

others

(including Lane and colleagues) have shown, the effects of DR to improve

glucoregulation and to support healthy insulin sensitivity appear to be

important

factors which decrease age-related morbidity and may lead to postponement of the

average age of death.

Lane and colleagues expressed concern that the animals' age of entry into the

study

was variable. The published paper noted that the data in the survival estimate

from

the proportional hazards model were left truncated; therefore, a monkey

contributed to the survival estimate at the age of entry to the laboratory. The

secondary analysis was important to compare metabolic subgroups and diet

treatment.

The results of this analysis, including the confidence intervals and the power

analysis, were clearly stated as preliminary and were included not as a final

authority on these issues but as preliminary findings of interest to the

research

field.

Regarding the normal monkeys, they were defined post hoc as those monkeys who

had

maintained normal fasting glucose and normal fasting insulin levels. Therefore,

it

is not surprising that the ad libitum-fed monkeys who remained metabolically

normal

would not be significantly different from the DR monkeys (who were also

metabolically normal), whereas the ad libitum-fed monkeys who developed

age-related

diseases (obesity, hyperinsulinemia, dyslipidemia, and/or diabetes) were more

likely

to die at a younger age than the DR monkeys. These findings were possible due to

the

large number of ad libitum-fed monkeys included in the study.

To our knowledge, our paper was the first to present detailed findings and

analyses

regarding the age at death, major cause of death, and organ pathology present at

death for both ad libitum-fed and DR primates who died during study. We believe

that

this pathology information is valuable to the scientific community and can

assist

greatly in the design of future studies of the mechanisms by which DR leads to

delayed onset of age-related diseases and decreased morbidity.

Lane and colleagues questioned the relevance and applicability of our findings

to

humans and to the likely effects of DR in humans. Ad libitum food intake is the

normal practice of most Americans today and obesity-associated disorders in the

United States are estimated to cost billions of dollars annually, with untold

effects on decreased quality of life to millions of affected individuals. The

consequent effects of obesity in humans on increased morbidity and age-related

diseases are therefore clear. We believe that the weight-clamp protocol

described in

our study is ideally suited to humans who can use a bathroom scale to encourage

the

prevention of obesity and improve health.

The current study of DR in primates provides important information on the causes

of

death in primates under ad libitum feeding versus DR, and the possible extension

of

the average age of death in primates that maintain a lean adult body weight free

of

obesity. We propose that the number of monkeys and the richness of data

collected

over many years of study during the life of the primate and at death provide

important insight into the relationship of diet, metabolic disorders, and aging

with

a clear and provocative relevance to healthy aging in humans as well.

References

Bodkin N, T, Ortmeyer H, E, Hansen B. Mortality and

morbidity

in laboratory-maintained rhesus monkeys and effects of long-term dietary

restriction. J Gerontol A Biol Sci. 2003;58A:212-219.

Hansen BC, Ortmeyer HK, Bodkin NL. Prevention of obesity in middle-aged

monkeys:

food intake during body weight clamp. Obes Res. 1995;3:199S-204S.[Abstract]

Masoro EJ, Mc RJM, Katz MS, McMahan CA. Dietary restriction alters

characteristics of glucose fuel use. J Gerontol Biol Sci. 1992;47:B202-B208.

Lane M, Ball SS, Ingram DK, et al. Diet restriction in rhesus monkeys lowers

fasting and glucose-stimulated glucoregulatory endpoints. Am J Physiol.

1995;268:(5

Pt 1): E941-E948.[Medline]

Kemnitz JW, Roecker EB, Weindruch R, Elson DF, Baum ST, Bergman RT. Dietary

restriction increases insulin sensitivity and lowers blood glucose in rhesus

monkeys. Am J Physiol. 1994;266:E540-E547.[Medline]

Bodkin NL, Ortmeyer HK, Hansen BC. Long-term dietary restriction in

older-aged

rhesus monkeys: effects on insulin resistance. J Gerontol A Biol Sci Med Sci.

1995;50:B142-B147.[Abstract]

Cefalu WT, Wagner JD, Wang ZQ, et al. A study of caloric restriction and

cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential

model

for aging research. J Gerontol A Biol Sci Med Sci. 1997;52:B10-B19.[Medline]

Lane M, Ingram D, Roth G. Calorie restriction in nonhuman primates: effects

on

diabetes and cardiovascular disease risk. Toxicol Sci. 1999;52:(Suppl):

41-48.[Abstract]

Gresl TA, Colman RJ, Roecker EB, et al. Dietary restriction and glucose

regulation in aging rhesus monkeys: a follow-up report at 8.5 yr. Am J Physiol

Endocrinol Metab. 2001;281:E757-E765.[Abstract/Free Full Text]

Lane MA, Mattison JA, Roth GS, Brant LJ, Ingram DK.

Effects of long-term diet restriction on aging and longevity in primates remain

uncertain.

J Gerontol A Biol Sci Med Sci. 2004 May;59(5):405-7. No abstract available.

PMID: 15123747

Al Pater, PhD; email: old542000@...

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