Creatine & Sarcopenia

Sarcopenia describes the characteristic loss of muscle mass that occurs with old age. Sarcopenia may arise from a combination of many factors:

  • Poor nutrition, in particular with reference to protein intake.
  • A reduction in cellular metabolic efficiency.
  • A reduced effectiveness in central nervous communication with peripheral musculature.
  • Reduced blood flow to muscles due to atherosclerosis.
  • Increased levels of proinflammatory cytokines.
  • Accumulated cellular damage due to reactive oxygen species.
  • Impaired neutralization of toxins by the liver.
  • Insufficiencies in muscle regeneration, possibly due to a depletion of the muscle stem cell pool.
  • Inactivity due to accumulated trauma/disease or decreased central nervous system drive.
  • Most importantly, an age-related decline in anabolic hormone status namely, testosterone, growth hormone and the insulin-like growth factors.

Given that new evidence has recently emerged indicating that creatine supplementation promotes the endogenous production of insulin-like growth factor type 1 (IGF-1) by muscle, it is quite feasible that creatine supplementation may serve to slow the progression of sarcopenia.

Creatine May Help Delay Sarcopaenia: An Age-Related Reduction in the Insulin-Like Growth Factors (IGFs)

Sarcopenia literally means the ‘loss of flesh‘ in Greek – sarx (flesh) penia (loss). Recent scientific studies suggest that creatine supplementation may help prevent the loss of muscle mass that is associated with advanced age, or sarcopenia – also spelt sarcopaenia.

Age-Related Decline in IGFs Produces Sarcopenia: Sarcopenia largely arises from an age-related decline in the production of our major anabolic hormones, namely testosterone, growth hormone and to a greater degree the Insulin-Like Growth Factors Types 1 and 2, or IGF-1 and IGF-2. Most evidence is leaning towards the greater importance of IGF-1 for muscle development and recovery. IGF-2, on the other hand, appears to play its predominant role during prenatal development.

Transgenic Mice – Proof That IGF-1 Postpones Sarcopenia: Transgenics, the technology of introducing exogenous genes into animals, has provided the most striking evidence for the importance of IGF-1 for prenatal muscle development and muscle regeneration in the adult. Transgenic mice that over-express the IGF-1 gene display greater amounts of muscle mass at birth, possess more lean muscle mass throughout life, as well as exhibit heightened regenerative capacity in old age (Ref. 4). Whereas older mice not possessing the transgene are unable to regenerate muscle in response to injury, old transgenic mice are quite capable of launching a robust phase of regeneration very soon after an insult.

Influence of Exercise: Inactivity is another factor that contributes to the development of sarcopenia. Importantly, physical activity increases IGF-1 production and hence, preserves muscle mass. Sarcopaenia can thus be partially counteracted with regular exercise.

Fast twitch (type II) muscle fibers, those that respond most robustly to creatine supplementation, are also those that are most sacrificed by sarcopenia (see also Muscle Specificity of Creatine Supplementation). Moreover, histological examination has shown IGF-1 localizes to fast twitch muscle fibers, indicating that part of the body’s IGF-1 allotment arises directly from fast twitch muscle fibers.

Therefore, creatine supplementation, by simply prolonging the work output of fast twitch muscle fibers, should maintain more youthful IGF-1 levels in the elderly and as a result, help counteract sarcopenia. This is just one possibility.

Another potential avenue for anabolic benefit attributed to IGF-1 is the improvement in cellular methylation capacity brought on by creatine supplementation. Muscle cells with heightened methylation status may produce IGF-1 longer into later life. Yet, another possibility is the muscle cell volumizing somehow switches on the gene responsible for producing IGF-1. Ongoing research will soon reveal which of these anabolic mechanisms are most sensitive to creatine supplementation.

See Creatine and Cellular Anabolics for more details about these other anabolic attributes of creatine.

Creatine Supplementation Directly Activates IGF-1 Production by Muscle:
Remaining to be shown was that creatine supplementation (via any combination of the above anabolic mechanisms) increases muscular IGF expression. Indeed, the first studies to this effect appeared just recently (2004) and demonstrated that treatment with creatine monohydrate induced IGF-1 expression in both muscle cells maintained outside the animal (Ref. 1, 2) as well as in human subjects under resting conditions (Ref. 3). You can imagine the excitement in the science-of-aging community when the first study appeared (Ref. 3) showing that creatine supplementation increases serum IGF-1 levels in humans.

These three studies clearly demonstrated that an exercise stimulus was not necessary in order for creatine treatment to provoke the production of IGF-1 directly by skeletal muscle cells. The first two in vitro (tissue culture) studies (Ref. 1 and 2) were performed on muscle cells maintained in plastic tissue culture dishes and therefore, not actively contracting, whereas the third study showed that IGF-1 levels could increase in non-exercising subjects following creatine supplementation (Ref. 3). Moreover, training only produced modest changes in IGF-1 levels over that observed in human subjects administered a placebo drink.

Finally, the two in vitro studies clearly demonstrate that creatine treatment causes muscle cells to directly produce IGF-1 in the absence of growth hormone, the anabolic hormone that has been traditionally ascribed with the role of stimulating IGF-1 production by the liver (see next section).

The hope is that creatine supplementation, by increasing the resting levels of IGF-1, may serve to slow the development of sarcopaenia in the elderly.

Those wishing to make the most of creatine’s anabolic potential are kindly referred to Creatine: A practical guide.

Selected Scientific References

Creatine Supplementation Increases Muscle Insulin-Like Growth Factor (IGF) Expression

Below are references to the two most definitive studies showing that creatine supplementation increases muscle IGF levels independently of an exercise stimulus. The last study was conducted in humans, whereas the other two studies employed a mouse muscle cell line maintained in tissue culture.

(Ref. 1) Louis, M. et al., (2004) Creatine increases IGF-1 and myogenic regulatory factor mRNA in C2C12 cells. Federation of European Biochemical Societies Letters, Volume 557, pages 243–247.

(Ref. 2) Deldicque, L. et al., (2007) Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways. American Journal of Physiology; Cell Physiology, Volume 293, pages C1263–C1271.

(Ref. 3) Deldicque, L. et al., (2005) Increased IGF mRNA in human skeletal muscle after creatine supplementation. Medicine & Science in Sports and Exercise, Volume 37 (5), pages 731–736.

Read our recent newletter detailing the direct effect that creatine supplementation has over muscle IGF production.

Selected Scientific References

Insulin-Like Growth Factor (IGF) Attenuates Muscle Loss in Old & Dystrophic Mice

Below is the reference to the mouse transgenic (IGF) study referred to above.

(Ref. 4) Musarò, A. et al., (2001) Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nature Genetics, Volume 27, pages 195–200.

Here is a reference to the study showing that IGF overexpression (via a transgenic approach) mitigates muscle loss in the mdx dystrophic mouse.

(Ref. 5) Barton, E. R. et al., (2002) Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. Journal of Cell Biology, Volume 157 (1), pages 137–148.

IGF over-expression has also been shown to greatly curb muscle degeneration and promote muscle regeneration in the mdx mouse, a mouse model for human muscular dystrophy, providing further impetus for creatine supplementation in individuals inflicted with muscular dystrophy (see Creatine Alleviates Symptoms of Muscular Dystrophy, also see Ref. 5); recall, we previously presented evidence that creatine supplementation augments muscular IGF expression.

Other Nutrients Known to Increase Serum Insulin-Like Growth Factor-1 (IGF-1) Levels

Zinc (10 milligrams/day)
Acetyl-L-carnitine (3 grams/day)
Vitamin D3 (2 micrograms/day)

Not by accident, infections reduce serum IGF-1 levels making muscle growth more difficult, whereas zinc boosts systemic immunity possibly creating a more permissive physiologic environment for muscle growth.

Selected Scientific Review

This is a highly recommended review article detailing how the body regulates its levels of IGF-1 and its involvement in muscle growth.

Frost, R. A. and Lang, C. H. (2003) Regulation of insulin-like growth factor-1 in skeletal muscle and muscle cells. Minerva Endocrinologica, Volume 28, pages 53-73.

Read a summary of the ongoing clinical trials examining the potential benefits of creatine supplementation in combating certain human diseases.

Creatine, Aging and Growth Hormone

The first recognized stimulus for the production of the insulin-like growth factors was the release of growth hormone from the Anterior Pituitary, a gland at the base of our brains. Growth hormone, in turn, is released from the anterior pituitary in response to exercise and deep sleep. Other less potent releasers of growth hormone include fasting, stress, injury, fever, infection as well as some neurotransmitters.

Once released, growth hormone stimulates the growth of bone and muscle as well as mobilizes lipids (fats) for energy usage. This dichotomous nature of growth hormone, provoking muscle and bone growth while causing our fat reserves to dwindle, is what makes many teenagers lean and lanky.

The total amount of growth hormone produced and subsequently released into the blood stream is a function of age. Growth hormone levels are highest during the growth spurt at adolescence, but thereafter commence to decline at a rate of about 14% per decade. In fact, the “pot-belly” that appears in many males in their 30s is a function of this age-related decline in growth hormone levels; recall, growth hormone mobilizes fat for energy usage while simultaneously causing bone and muscle to amass tissue. Sadly, as a result of the age-related decline in growth hormone levels, by 80 years of age, we are producing only 1/20 of the growth hormone levels we were once producing in our 20s!

The vast majority of growth hormone’s anabolic effects are mediated by the insulin-like growth factors (see the previous section). In this context, the appearance of growth hormone in the blood stream stimulates cells in the liver to synthesize IGF-1, which is then released into the systemic circulation to provoke the growth of bone and muscles as well as the absorption of our fat reserves.

Interestingly, one recent study provided evidence that creatine supplementation increases serum growth hormone levels, which, in turn, would increase the production of our insulin-like growth factors. It would thus appear that creatine supplementation augments the production of IGF-1 in two manners: 1) by stimulating the anterior pituitary to release growth hormone and; 2) by directly activating the endogenous production IGF-1 by muscle cells as explained in the previous section. The study that showed increased growth hormone release in response to creatine supplementation is given below.

Selected Scientific References

Creatine Supplementation Increases Serum Growth Hormone Levels

Below is a reference to a preliminary study suggesting that creatine supplementation may also increase serum growth hormone levels independently of an exercise stimulus. That is, at rest.

The amount of creatine monohydrate used in this study to evoke the resting release of growth hormone was a single dose of twenty grams. Although extremely provocative, this result needs to be corroborated by further scientific research.

Schedel J. M. et al., (2000) Acute creatine loading enhances human growth hormone secretion. Journal of Sports Medicine & Physical Fitness, Volume 40 (4), pages 336–342.

Importantly, increasing IGF levels through natural means (perhaps via creatine supplementation) is a much safer alternative than directly administering exogenous growth hormone, since this later practice has been repeatedly shown to produce some very serious side effects, including diabetes, hypertension and shortened life span.

A supplementing routine designed for senior citizens is given in Creatine: A practical guide.

More details about the roles of growth hormone and IGF-1 for muscle and bone development is provided.

Finally, it is now known whether IGF-1 levels also increase in response to steroidal agents, such as testosterone precursors. Thus far no effect of creatine supplementation over serum testosterone levels has been demonstrated.

Anabolic Warning!

Factors That Undermine the Release of Growth Hormone

Consuming alcohol soon before sleep interferes with the progression through the REM phases of sleep and consequently, reduces the nocturnal release of growth hormone. Athletes should thus avoid alcohol consumption immediately before going to bed, as this will greatly undermine the potential anabolic benefits of growth hormone. Finally, to fully capitalize on the nocturnal release of growth hormone, athletes should also make certain to get a full night’s sleep.

Our major catabolic hormone, cortisol, also reduces growth hormone release. Therefore, excessive exercise (which produces cortisol) will also interfere with muscle growth by negatively influencing the release of growth hormone from the Anterior Pituitary gland and contributing to a catabolic condition known as Overtraining Syndrome, or OTS. Fortunately, certain nutritional maneuvers are available to help mitigate the release of cortisol and avoid OTS.

Therefore, adequate rest, smart training methods and proper nutrition are all requirements to creating a metabolic environment that is most conducive to muscle growth. How to optimize your anabolic status is discussed in Creatine: A practical guide.

Conjugated Linoleic Acids Broaden Creatine’s Range of Benefits for the Elderly

Reduced muscle content and augmented fat reserves are characteristic of advanced age. A recent study has demonstrated that a supplementing regimen consisting of creatine monohydrate and conjugated linoleic acids increases strength and reduces body fat following six months of modest resistance training in men and women between 65 and 85 years of age.

Selected Scientific References

The Combination of Creatine and Conjugated Linoleic Acids Increases Strength and Reduces Body Fat

Conjugated linoleic acids (CLAs) have been previously shown to reduce body fat content in overweight individuals. This recent study showed that combining CLA and creatine supplementation increases lean muscle mass and reduces body fat in elderly individuals in response to modest resistance training.

Tarnopolsky M. et al., (2007) Creatine monohydrate and conjugated linoleic acid improve strength and body composition following resistance exercise in older adults. PLoS ONE, Volume 2 (10), pages e991.

Learn more about the benefits of this special combination of creatine and conjugated linoleic acids for the elderly .

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