Life Extension Magazine December 2012
Age-Related Metabolic Decline and Weight Gain
By Michael Downey
A mechanism long known to contribute to age-related weight gain is a decrease in resting metabolic rate1—the number of calories burned when the body is at rest. This can lead to significant weight gain—even if you haven't changed your diet at all.1-4
To make matters worse, dieting can exacerbate the problem because it can lead to a further decrease in the resting metabolic rate.5-7
Obese and overweight individuals have a reduced life expectancy.8 They also have a greater risk of many disorders, including heart disease,9-11 dementia,12 osteoarthritis,13allergies,14,15 and diabetes.16
Scientists have uncovered several ways to reverse the decrease in metabolic rate that makes it so easy to accumulate weight and fat as we age. A double-blind, placebo-controlled study showed results in as little as 7 days.17
The Root of Age-Related Weight Gain
Most people tend to experience a reduction in their metabolic rate as they age, which can lead to the unhealthy accumulation of extra body fat.1-4,18,19 A wealth of evidence now suggests that this tendency to pack on pounds over time originates with changes in your body's relationship with calories:
- With age, your energy expenditure drops due to a decline in resting metabolic rate.3,4
- Aging may also cause a reduction in the conversion of stored body fat to energy.20
- There is an age-related reduction in fat-free mass in your body—which means a proportionate loss of this more metabolically active and energy-burning muscle tissue.2,18,19,21,22
- Attempts to lose excess weight trigger a decrease in resting metabolic rate— ironically contributing to continued weight gain.5-7
The ideal solution to this problem would be one that restores metabolic activity and supports the burning of fat.
Non-resting (active) metabolism uses only about 30% of total calories, and the generation of body heat requires only about 10% of calories.2 The other 60% of burned calories comes from your resting metabolic rate.2
So, scientists have known that even just a 2-3% increase in resting metabolic rate could have the effect of reversing age-related weight and fat gain!23
The challenge was to find a natural way to maintain body weight and resting metabolic rate without the cardiovascular or central nervous system side effects seen with stimulant-associated fat-burning agents.17,24
Researchers initially investigated DHEA (dehydroepiandrosterone) because age-related decreases in this hormone are associated with increased abdominal fat.25 From there, scientific attention began to focus on one of the many metabolites of DHEA—the chemical compound 3-acetyl-7-oxo-dehydroepiandrosterone, commonly called 7-Keto DHEA or simply 7-Keto.
There were several reasons for great interest in this metabolite:
- Like DHEA, studies showed that average blood concentrations of 7-Keto decline with age.26
- To a greater degree than DHEA, 7-Keto was found to raise metabolic rate and promote fat burning by boosting the activation of three thermogenic enzymes that stimulate fatty acid oxidation:
- Glycerol-3-phosphate dehydrogenase,
- Malic enzyme, and
- Fatty acyl CoA oxidase.27-30
- Although DHEA's effect on thyroid function is not clear, it is known that 7-Keto increases thyroid hormones, which are associated with increased resting metabolic activity.31
- Unlike DHEA, 7-Keto is not converted into estrogen or testosterone, making it safer for use by people with hormone-dependent conditions, such as prostate and breast cancers.30
Also, well-controlled research on healthy, human volunteers found daily administration of 7-Keto to be very well-tolerated.24
So 7-Keto supplements appeared to be a safe and effective answer to the age-related decline of resting metabolic rates.
To verify these benefits, scientists set out to confirm if 7-Keto supplementation induces an increase in resting metabolic rate. They conducted a clinical trial of the most rigorous type…a randomized, double-blind, placebo-controlled study on humans.
Restoring Resting Metabolic Rate In as Little as 7 Days
Because the age-related decrease in metabolism takes place over many years, scientists needed to find a way to study metabolic slowdown over a shorter period. In order to achieve this effect, they set up a clinical study in which volunteers were placed on a calorie-restricted diet—a known trigger for a decreased resting metabolic rate.5-7
In this randomized, double-blind, placebo-controlled study, researchers used a cross-over design in which a group of overweight volunteers took 7-Keto during one phase and a placebo during another phase. In this type of study, the subjects essentially act as their own control group, which produces more reliable observations.
As expected, the metabolic effect of the calorie-restricted diet triggered a decrease in resting metabolic rate of 3.9% during the placebo phase.17
However, 7-Keto supplements taken twice daily reversed this 3.9% decrease and further increased resting metabolic rate by 1.4% above the baseline level—in just 7 days!17
This represented an overall increase of 5.3% in energy consumption—equivalent to about 96 extra calories burned per day—but with no change in exercise levels. This indicated that 7-Keto supplements can increase resting metabolic rate—and within a 7-day period!
The observed 5.3% increase in resting metabolic rate exceeded the 2-3% increase that scientists had previously speculated would be sufficient to help reverse age-related weight gain.23
Also, 7-Keto supplements were found in this study to have no cardiovascular or central nervous system side effects.17 This confirmed earlier research demonstrating that 7-Keto was safe and well-tolerated.24, 32-34
Although this research established the ability of 7-Keto to increase resting metabolic rate—suggesting it would also help prevent age-related weight gain—scientists conducted additional placebo-controlled studies in order to measure the precise impact of 7-Keto supplements on weight.
Metabolically Induced Weight Loss
Supplementation with 7-Keto raises resting metabolic rate, which in turn would be expected to produce weight loss.17,23,35 To verify this result, scientists enlisted 30 healthy, overweight adults with an average age of 44.5 years, in a randomized, double-blind, placebo-controlled study. They were randomly divided into two groups.
Half of the participants were given 100 mg of 7-Keto twice daily, while the other half were given a placebo. Both groups followed a diet of 1,800 calories a day and took part in 60 minutes of exercise training three times per week.
After 8 weeks, the 7-Keto subjects lost an average of 6.34 pounds versus an average of 2.13 pounds in the control group. The 7-Keto participants also lost over 3 times more body fat than the control subjects—1.8% vs. 0.56%. An increase in thyroid hormone activity was observed in the 7-Keto group, which targets fat-burning genes in the mitochondria and adipose tissue. 7-Keto did not adversely affect thyroid function and no negative effects were found.35
Because there were no significant differences between the two groups in terms of overall calorie intake or total calorie expenditure, the study concluded that 7-Keto induces weight loss.35
Scientists then conducted a second randomized, double-blind, placebo-controlled trial to assess the effects of a formulation containing 7-Keto on overweight subjects. The formulation contained no ingredients with proven weight-loss effects except 7-Keto.
The treatment group received 200 mg a day of the 7-Keto formulation, while the control group received a placebo. All participants were placed on a weight-reduction diet of 1,800 calories a day and were monitored in an exercise program. Within 8 weeks, the 7-Keto group lost an average of 4.73 pounds—compared to 1.58 pounds lost by the control group. The 7-Keto group also decreased their body mass index (BMI) score by an average of 0.71, a much greater improvement than the average BMI reduction of 0.01 among the control subjects. 7-Keto was well tolerated and no significant side effects were found.36
As in the previous study, there were no significant differences between the two groups in terms of calories consumed or expended. These results confirmed that supplementation with 7-Keto produces weight loss.36
Four More Anti-Aging Benefits
Beyond its ability to reverse the age-related decrease in resting metabolic rate—and ultimately help produce weight loss—7-Keto has been shown to deliver a number of other anti-aging dividends, ranging from boosting weakened immune function to improving memory.
Enhanced Immune System
The thymus atrophies after adolescence, shrinking to about 15% of its maximum size by middle age. Since immune cells called T-cells mature in the thymus, T-cell function decreases with this age-related shrinkage.37 Soon, parts of the immune system become weakened, substantially reducing our ability to avoid infections and autoimmune responses.37
Scientists found indications that 7-Keto has immune-boosting effects in an in vitro study of spleen lymphocytes from mice. An immune-suppressing drug was introduced, which as expected, dramatically reduced lymphocyte levels. But when 7-Keto was added, lymphocyte viability increased by 95-117%. In addition, a measure of primary immune response increased by 120-150%.38
7-Keto was shown in a lab study of human lymphocyte cells to enhance the production of interleukin-2.39 Interleukin-2 is an important type of signaling molecule that stimulates the production of various T-lymphocytes, which in turn stimulates production of other immune system agents.40 The capacity of 7-Keto to increase interleukin-2 suggested it may offer strong immune-enhancing benefits against a wide range of conditions, including major diseases such as cancer and AIDS.39
A team of scientists then exposed mice with compromised immune systems to four weeks of mild, chronic stress. This resulted in a decrease in their white blood cell proliferative response and a decrease in thyroid hormone levels. However, when the mice were given 7-Keto, their white blood cell proliferative response was greatly increased, natural killer cell activity was dramatically enhanced, and thyroid levels increased to normal levels.41
These intriguing results led to a 7-Keto study on humans.
In a randomized, double-blind, placebo-controlled study enlisting 22 women and 20 men over the age of 65, the treatment group took 100 mg of 7-Keto twice daily, while the controls took a physically identical placebo. After four weeks, subjects in the 7-Keto group showed a significant increase in immune helper cells, decrease in immune suppressor cells, and increase in neutrophils, the first white blood cells to respond to an infection.42 (Note that excess levels of immune suppressor cells can prematurely turn critical immune functions "off", so suppressing them is of importance in individuals seeking enhanced immune activity.)
Improved Cholesterol Profile
The age-related decline in resting metabolic rate can lead to obesity and an increase in levels of harmful low-density lipoprotein or LDL cholesterol.43
When LDL cholesterol increases—and is not offset by a greater increase in high-density lipoprotein or HDL cholesterol—it results in a higher atherogenic index. This is the ratio of total cholesterol to HDL, and a higher ratio represents a higher risk of cardiovascular disease and heart attack.
Scientists tested the effect of 7-Keto on the cholesterol profiles of 10 human subjects. Volunteers aged 27 to 72 applied a gel containing 7-Keto to their abdominal skin for 5 days consecutively. This delivered 25 mg of 7-Keto.
While there was only a very modest decrease in total cholesterol, there was a "strongly significant" improvement in cholesterol composition. Harmful LDL cholesterol levels decreased slightly, and HDL cholesterol levels rose significantly. Together, these changes produced a strong reduction—meaning improvement—in the atherogenic index. There was also an increase in beneficial apolipoprotein A-1, a protector of cardiovascular health.44
These benefits were observed after administration of just 25 mg of 7-Keto—a relatively small dose.44
Reversed Memory Decline
Normal aging is associated with age-related memory impairment—a decline in various memory abilities that includes a decrease in the ability to encode new memories.45 7-Keto supplementation may be able to reverse this age-related memory loss.
Scientists trained young mice to use a water maze. They then experimentally induced memory loss. A subsequent single injection of 7-Keto—at 24 mg per kg of body weight (equivalent to 144 mg for a 165 pound adult)—reversed the memory deficit.46
The team then fed 7-Keto to old mice that had learned the maze. The 7-Keto mice were able to retain their memory of the maze for the entire 4-week test period—while old mice not receiving 7-Keto lost their memory of the task.46
Clinical studies are still needed to confirm this reversal of age-related memory decline in humans, but the results of these animal studies are encouraging.
General Anti-Aging Benefits
Research conducted on DHEA (dehydroepiandrosterone)—the hormone that produces 7-Keto as a metabolite—produced a number of general anti-aging effects from replacement of age-diminished DHEA levels.
Elderly human volunteers were given 50 mg of DHEA daily. After 3 months, scientists found increased levels of anabolic growth factor and greater lean body mass, muscle strength, immune function, and quality of life. Both men and women reported improvements in physical and psychological well-being, energy, mood, sleep patterns, relaxation feelings, and the ability to deal with stress.47
DHEA is converted by the body into androstenedione, which is then converted into the male and female sex steroid hormones, estrogen and testosterone. This conversion is highly individualized and some people could end up with excess levels of these sex hormones—which could pose a risk if any of those individuals have a hormone-dependent disease, such as prostate or breast cancer.30,48
Unlike DHEA however, 7-Keto does not trigger higher sex hormone levels.44 That means that supplementing with 7-Keto may be a safer way for some people to benefit from these anti-aging effects including enhancing the immune system, reducing age-related memory loss, and improving cholesterol profiles.
Advancing age causes a significantly decreased resting metabolic rate.1 This can lead to age-related increases in body fat1-4,18,19 along with increased risk of heart disease,9-11 diabetes,16 and dementia.12Aging individuals often find themselves overweight or obese1-4,18,19—which means a reduced life expectancy.8
Unfortunately, dieting can trigger a further metabolic slowdown.5-7
Fortunately, scientists have found that replenishing the levels of a DHEA metabolite known as 7-Keto reverses the age-related decrease in metabolic rate in just 7 days.17 This translates into reductions in weight and body mass index in just 8 weeks!35,36
It would appear those seeking to lower their calorie intake would enjoy greater reduction of body fat mass by supplementing with 100 mg of 7-Keto twice a day.
Best of all, 7-Keto has other anti-aging benefits—including enhancing immune function, reducing age-related memory loss, and improving cholesterol profiles.38,43,46
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
1. Fukagawa NK, Bandini LG, Young JB. Effect of age on body composition and resting metabolic rate. Am J Physiol. 1990 Aug;259(2 Pt 1):E233-8.2.
2. St-Onge MP, Gallagher D. Body composition changes with aging: the cause or the result of alterations in metabolic rate and macronutrient oxidation? Nutrition. 2010 Feb;26(2):152-5. Epub 2009 Dec 8.
3. Luhrmann PM, Edelmann-Schafer B, Neuhauser-Berthold M. Changes in resting metabolic rate in an elderly German population: cross-sectional and longitudinal data. J Nutr Health Aging. 2010 Mar;14(3):232-6.
4. Rising R, Tataranni PA, Snitker S, Ravussin E. Decreased ratio of fat to carbohydrate oxidation with increasing age in Pima Indians. J Am Coll Nutr. 1996 Jun;15(3):309-12.
5. de Jonge L, Bray GA, Smith SR, et al. Effect of diet composition and weight loss on resting energy expenditure in the pounds lost study. Obesity (Silver Spring). 2012 May 7. [Epub ahead of print].
6. Apfelbaum MJ, Bestsarron J, Lacatis D. Effect of caloric restriction and excessive caloric intake on energy expenditure. Am J Clin Nutr. 1971;24:1405-9.
7. Connolly J, Romano T, Patruno M. Selections from current literature: effects of dieting and exercise on resting metabolic rate and implications for weight management. Fam Pract. 1999 Apr;16(2):196-201.
8. Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-Mass Index and mortality among 1.46 million white adults. N Engl J Med. Dec 2010;363(23):2211-9.
9. Persic V. Obesity in the cardiovascular continuum. Curr Clin Pharmacol. 2012 Sep 3. [Epub ahead of print]
10. Park YS, Kim JS. Obesity phenotype and coronary heart disease risk as estimated by the Framingham risk score. J Korean Med Sci. 2012 Mar;27(3):243-9. Epub 2012 Feb 23.
11. Franco M, Orduñez P, Caballero B, et al. Impact of energy intake, physical activity, and population-wide weight loss on cardiovascular disease and diabetes mortality in Cuba, 1980-2005. Am J Epidemiol. 2007 Dec 15;166(12):1374-80.
12. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008 Sep 30;71(14):1057-64.
13. Roemer FW, Zhang Y, Niu J, et al. Tibiofemoral joint osteoarthritis: Risk factors for MR-depicted fast cartilage loss over a 30-month period in the Multicenter Osteoarthritis Studies. Radiology. 2009 Sep;252(3):772-80.
14. Visness CM, London SJ, Daniels JL, et al. Association of obesity with IgE levels and allergy symptoms in children and adolescents: results from the National Health and Nutrition Examination Survey 2005-2006. J Allergy Clin Immunol. May 2009;123(5):1163-9,1169.e1-4.
15. Chu YT, Chen WY, Wang TN, Tseng HI, Wu JR, Ko YC. Extreme BMI predicts higher asthma prevalence and is associated with lung function impairment in school-aged children. Pediatr Pulmonol. 2009;44(5):472-9.
16. Catenacci VA, Hill JO, Wyatt HR. The obesity epidemic. Clin Chest Med. 2009 Sep;30(3):415-44,vii.
17. Zenk JL, Frestedt JL, Kuskowski MA. HUM5007, a novel combination of thermogenic compounds, and 3-acetyl-7-oxo-dehydroepiandrosterone: each increases the resting metabolic rate of overweight adults. J Nutr Biochem. 2007 Sep;18(9):629-34.
18. Kyle UG, Genton L, Hans D, Karsegard L, Slosman DO, Pichard C. Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. Eur J Clin Nutr. 2001 Aug;55(8):663-72.
19. Mazariegos M, Wang ZM, Gallagher D, et al. Differences between young and old females in the five levels of body composition and their relevance to the two-compartment chemical model. J. Gerontol. 1994;49:M201-8.
20. Perichon R, Bourre JM. Liver peroxisomal fatty acid oxidizing system during aging in control and clofibate-treated mice. Biochem Mol Biol Int. 1995;37(3):475-80.
21. Kyle UG, Genton L, Hans D, et al. Total body mass, fat mass, fat-free mass, and skeletal muscle in older people: cross-sectional differences in 60-year-old persons. J Am Geriatr Soc. 2001 Dec;49(12):1633-40.
22. Janssen I, Ross R. Linking age-related changes in skeletal muscle mass and composition with metabolism and disease. J Nutr Health Aging. 2005 Nov-Dec;9(6):408-19.
23. Astrup A. Thermogenic drugs as a strategy for treatment of obesity. Endocrine. 2000;13:207-12.
24. Davidson M, Marwah A, Sawchuk RJ, et al. Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers. Clin. Invest. Med. 2000;23(5):300-10.
25. Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA. 2004 Nov 10;292(18):2243-8.
26. Marenich LP. Excretion of testosterone, epitestosterone, androstenedione and 7-ketodehydroepiandrostenedione in healthy men of different ages. Probl Endokrinol (Mosk). 1979 Jul;25(4): 28-31.
27. Lardy H, Kneer N, Wei Y, Partridge B, Marwah P. Ergosteroids II: Biologically active metabolites and synthetic derivatives of dehydroepiandrosterone. Steroids. 1998 Mar; 63(3):158-65.
28. Bobyleva V, Kneer N, Bellei M, Battelli D, Lardy HA. Concerning the mechanism of increased thermogenesis in rats treated with dehydroepiandrosterone. J Bioenerg Biomembr. 1993 June;25(3):313-21.
29. Bobyleva V, Bellei M, Kneer N, Lardy H. The effects of the ergosteroid 7-oxo-dehydroepiandrosterone on mitochondrial membrane potential: possible relationship to thermogenesis. Arch Biochem Biophys. 1997 May;341(1):122-8.
30. Lardy H, Partridge B, Kneer N, Wei Y. Ergosteroids: induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone. Proc Natl Acad Sci USA. 1995 July;92(14):6617-9.
31. Hampl R, Sulcová J, Bílek R, Hill M. How short-term transdermal treatment of men with 7-oxo-dehydroepiandrosterone influence thyroid function. Physiol Res. 2006;55(1):49-54. Epub 2005 Apr 26.
32. Davidson M. Safety and pharmacokinetic study with escalating doses of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers. Clin Invest Med. 2000 Oct;23(5):300-10.
33. Lardy H, Henwood SM, Weeks CE. An acute oral gavage study of 3-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in rats. Biochem Biophys Res Comm. 1999;254:120-3.
34. Henwood SM, Weeks CE, Lardy H. An escalating dose oral gavage study of 3-acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in rhesus monkeys. Biochem Biophys Res Comm. 1999;254:124-8.
35. Kalman DS, Colker CM, Swain MA, Torina GC, Shi Q. A randomized, double-blind, placebo-controlled study of 3-acetyl-oxo-dehydroepiandreosterone in healthy overweight adults. Curr Therap Res. 2000;61(7):435-42.
36. Zenk JL, Helmer TR, Kassen LJ, Kuskowski MA. The effect of 7-Keto NaturaleanTM on weight loss: a randomized, double-blind, placebo-controlled trial. Curr Ther Res. 2002;63:263-72.
37. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/004008.htm. Accessed September 19, 2012.
38. Hampl R, Lapcik O, Hill M, et al. 7-Hydroxydehydroepiandro-sterone—a natural antiglucocorticoid and a candidate for steroid replacement therapy? Physiol Res. 2000;49 Suppl 1S107-12.
39. Nelson R, Herron M, Weeks C, Lardy H. Dehydroepiandrosterone and 7-keto DHEA augment interleukin 2 (IL2) production by human lymphocytes in vitro. The 5th Conference on Retroviruses and Opportunistic Infections. Chicago, IL. Feb1998;598:49.
40. Whittington R, Faulds D. Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer. Drugs. Sep 1993;46(3):446-514.
41. Liu YY, Yang N, Kong LN, Zuo PP. Effects of 7-oxo-DHEA treatment on the immunoreactivity of BALB/c mice subjected to chronic mild stress. Yao Xue Xue Bao. 2003 Dec;38(12):881-4.
42. Zenk JL, Kuskowski MA. The use of 3-acetyl-7-oxo-dehydroepiandrosterone for augmenting immune response in the elderly. Presented at meeting of FASEB, April 17, 2004.
43. Available at: http://orthoinfo.aaos.org/topic.cfm?topic=A00191. Accessed September 19, 2012.
44. Sulcova J, Hill M, Mazek Z, et al. Effects of transdermal application of 7-oxo-DHEA on the levels of steroid hormones, gonadotropins and lipids in healthy men. Physiol Res . 2001;50(1):9-18.
45. Miller SL, Celone K, DePeau K, et al. Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation. Proc Natl Acad Sci USA. 2008 Feb 12;105(6):2181-6. Epub 2008 Jan 31.
46. Shi J, Schulze S, Lardy HA. The effect of 7-oxo-DHEA acetate on memory in young and old C57BL/6 mice. Steroids. 2000 Mar;65(3):124-9.
47. Yen SS, Morales AJ, Khorram O. Replacement of DHEA in aging men and women. Potential remedial effects. Ann N Y Acad Sci. Dec1995;774:128-42.
48. Available at: http://www.nia.nih.gov/health/publication/can-we-prevent-aging. Accessed September 19, 2012.
49. Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect Dis. Aug 2000;31(2):578-85.