Sarcopenia

We mostly associate osteoporosis and the resultant fractures as the one of the most debilitating conditions as we age and in the elderly. However, it has been suggested that no decline with age is as dramatic or potentially more significant than the decline in lean body mass(1). This age related loss of lean body mass is termed sarcopenia – a combination of the Greek words sarx, meaning “flesh”, and penia, meaning “loss”. It is estimated that 25% of individuals over the age of 64 suffer from sarcopenia (2).  With an estimated 2 billion people over the age of 60 by 2050 sarcopenia will most likely become a more prevalent and debilitation musculoskeletal condition in the elderly perhaps even surpassing osteoporosis (3).

The underlying mechanisms of sarcopnia are multifactorial with any or all of the following contributing factors causing loss of muscle cell mass:

• Pro-inflammatory cytokines released from fat cells
• Increased reactive oxygen species (ROS) and decreased dietary antioxidants
• Aging related declining hormones
• Insulin resistance
• Inadequate protein intake and decreased protein synthesis
• Decreased physical activity, lack of cognitive function and mobility

Pro-inflammatory cytokines released from fat cells

We are at a point in history where we have over a billion people classified as overweight. The progression of modern man is from robust muscular manual worker of perhaps our grandfather’s generation to sedentary overweight and obese man of today. This excess body fat we are accumulating is not just an inert substance that sits on our love handles acting as a reservoir of energy to be called upon the next time we decide to run a half marathon or play a football game. It acts as an endocrine organ releasing an array of hormones and pro and anti-inflammatory cytokines into the body (4).

Most notably in sarcopenia it is the excess release of inflammatory cytokines IL-1 beta, IL-6 and TNF alpha that signals to the muscle cell to self destruct – a process known as apoptosis leading to cell mass loss (2). The term that is now being used to describe this process is sarcopenic obesity – whereby increased fat mass releases inflammatory cytokines that drives muscle cell apoptosis.  Fat cells also release an excess of plasminogen activator inhibitor- (PAI-1) that promotes angiogenesis, arthrogenesis and thrombosis; adipsin that increases the uptake of fatty acids, increases triglyceride synthesis and transports glucose into fat cells turning it to fat; renin and angiotensin, both of which increase vascular tone and increase blood pressure; and TNF alpha, IL-6 and resistin that promote inflammation. These processes increase fat mass, blood pressure and insulin resistance leading to what has been termed metabolic syndrome.

Fat cells also contain an enzyme called aromatase that converts testosterone to oestrogen (4). This is a perfect mechanism for males who need a little bit of oestrogen to help maintain bone mineral density and for post menopausal females to maintain oestrogen output after the ovaries have reduced their function. However in over weight and obese people who have an excess of aromatase activity creating an excess of oestrogen there could be endocrine related disorders such as a declining testosterone levels that is considered a risk factor for sarcopenia (2) and the development of breast and prostate cancer (5).

Fat cells also release leptin that signals to the brain you are full. However in obesity this signalling mechanism goes awry. Leptin levels can become extremely high in obese people leading to leptin resistance, a condition much like insulin resistance where lots of leptin is in the blood but your brain doesn’t respond to it any more (4). Therefore you don’t feel full and carry on over eating. Increased leptin also causes increased insulin production and can exacerbate insulin resistance and can up-regulate MMP activity, ROS formation and inflammation contributing to conditions such as osteoarthritis (6).

Increased reactive oxygen species (ROS) and decreased dietary antioxidants

Another mechanism at play is the increased free radical damage that occurs with inflammation. The pro-inflammatory cytokines released from adipose tissue such as TNFα activate a signalling pathway in the muscle cells that culminates in the activation of nuclear factor κB (NF-κB). NF-κB is a cell signalling intermediary that takes part in the immune and inflammatory responses, If up-regulated it can promote inflammation. In this instance NF-κB up regulates the production of inducible nitric oxide synthase (iNOS), an enzyme that in the cytosol of the muscle cell converts arginine into citrulline, releasing nitric oxide (NO). Nitric oxide can diffuse out of the cells where it can combine with superoxide (O2-) to form peroxynitrite (ONOO-). Peroxynitrite can then diffuse back into the cell membrane oxidising the fatty acids in the cell membrane creating lipid peroxides as well diffusing into the cytosol and switching off cell signalling mechanisms that promote protein synthesis. The end result being muscle atrophy and muscle cell damage (2).

Declining hormones

The hormonal influence on muscle also plays a role in sarcopenia. Growth hormone (GH), insulin like growth factors (IGF1) and testosterone all have anabolic functions on muscle stimulating growth and repair whereas cortisol has a catabolic effect on muscle causing muscle breakdown and the shuttling of amino acids to the liver to produce glucose via gluconeogenesis. The balance between these anabolic and catabolic actions maintains the health of muscle. At the 2007 Summit of Environmental Challenges to Reproductive Health and Fertility it was established that testosterone levels have decreased 1% per year, every year for the last 50 years (7). Perhaps due to obesity and aromatase activity, ROS formation, stress levels or environmental pollution as we shall discuss later in this article. This decline in androgens and is one of a number of endocrine processes that can underlie the development of sarcopenia. Similar to women who go through menopause, males go through an andropause whereby GH, IGF’s and testosterone naturally decline with age. This decline in anabolic signals to the muscle tissue can lead to muscle atrophy.

In an effort to reduce body fat and to lose weight people start to exercise. It has long been observed that exercise affects the body in a dose dependent way – a phenomenon known as hormesis. This is where a low dose exposure to regular exercise has a positive effect on the body (such as the immune and endocrine systems), but whereby a high dose exposure has a negative effect.  High doses of prolonged activity especially when you have a busy stressful job can stimulate a catabolic state. These types of athletes would be the excessive gym goers, triathletes, long distance runners or people who get up at 5am to hit the gym before work. Especially if they are not monitoring their recovery status or periodising recovery periods into the training plan.

Both the stress and sex hormones are made from the same raw material – cholesterol which is then converted into pregnenalone and so on into the different metabolites –  anabolic androgens, and catabolic glucocorticoids as well as mineralcortisocoids in the adrenal glands and gonads. However in people who are stressed or over exercise pregnenalone steal occurs whereby the raw material that produces both the androgens and glucocortiscoids ends up going down the glucocorticoid pathway to produce cortisol – the main stress hormone. Again this will end up in lower androgens and lead to declining muscle mass. These hormones can be monitored through saliva testing and give an indication of training and recovery status for those wishing to monitor their endocrine status and periodise their training better.

We also need to acknowledge that as we age we are bombarded with messages to reduce cholesterol in an effort to reduce heart disease. This actually reduces the raw material for steroid hormone production as well as vitamin D synthesis. Clearly there needs to be balance between reducing cholesterol levels to prevent heart disease but also factoring in having enough to make steroid hormones and vitamin D.

Insulin resistance

There is now a huge body of evidence that links persistent organic pollutants (POPs) to diabetes. These POPs include pesticides, plastics such as phthalates and dioxins, bisphenol-A and parabens.  A study found a “striking” relationship between six POPs and diabetes in U.S. adults exposed to “normal” levels of POPs (8). PCBs and organochlorine pesticides were most strongly associated. The higher the levels of these POPs, the higher the prevalence of diabetes. Several prevalent phthalate metabolites also showed statistically significant correlations with abdominal obesity and insulin resistance (9). Abnormal levels of endogenous oestrogens or environmental oestrogen exposure also enhances the risk of developing type 2 diabetes (10).

When we understand the function of the pancreatic β-cell we can see how these POPs can lead to diabetes. The function of the pancreatic β-cell is the storage and release of insulin, the main hormone involved in blood glucose homeostasis. However oestrogen (both endogenous and exogenous) can also stimulate the beta cell to produce insulin. Thus the constant stimulation of the pancreatic β-cell from POPs leads to hyperinsulinemia and insulin resistance (11).

This in turn can predispose an individual to the development of sarcopenia. Insulin plays an important role in muscle amino acid uptake and protein synthesis (3). Thus insulin resistance decreases muscle amino acid uptake and anabolic signals from insulin and the branched chain amino acids. Sarcopenia is associated with insulin resistance in non-obese and obese individuals (12). There is data to suggests that insulin resistance precedes sarcopenia, and may therefore play a fundamental role in its development (13).

Inadequate protein intake and decreased protein synthesis

Is it well known that appetite, total calorie and protein intake can decline with age. Food intake can fall by as much as 25% between 40 and 70 years of age (14). Protein intake is still a contentious issue. There is the belief that eating a high protein diet leads to leaching of calcium from the bones and can lead to osteoporosis, and that higher protein intake damages the kidneys. The first theory is that the high sulphurous load of animal proteins cannot be handled by the kidneys and needs to be buffered by calcium that is recycled from bone tissue. However, few studies support this theory (15). A Systematic review and meta analysis by demonstrated that the relation between protein intake and bone mineral density (BMD) and bone mineral content (BMC) were significant and positive. The protein intake observed in these studies was from 0.9-1.7g/kg of body weight, with the majority of the studies being 1.2g/kg of body weight (16). As far as preventing osteoporosis is concerned some authors recommend that elderly people keep their protein intake up to and above 1g of protein per kg of body weight (17), and as muscle tissue is also made from protein we can take a leap of faith and suggest this protein intake be used to maintain muscle health as well.

The second theory that higher protein diets damage the kidneys also might not be supported by research findings. A low-carbohydrate high-protein weight-loss diet over 2 years was not associated with noticeably harmful effects on kidney function and electrolyte balance compared with a low-fat diet (18).

Decreased physical activity, lack of cognitive function and mobility

As we age there is an inevitable decline in physical activity and sometimes also a decline in cognitive function. This decline in exercise and mobility leads to a sedentary loss of muscle function and strength, bone mass and anabolic signal to the musculoskeletal system. Lack of mobility and also lack of outdoor activity can also lead to vitamin D deficiency; vitamin D is important for muscle and bone health and a deficiency can further impair strength and muscle mass.

Summary

Prevent and reduce the age related loss of muscle mass it would be advisable to:

• Maintain a good body composition (lean mass to fat mass)
• Eat adequate amount of protein and a diet rich in coloured vegetables and fruits to support insulin sensitivity, androgens and reduce ROS
• Eat as much organic produce as you can to decrease exposure to POPs
• Do resistance training and cardiovascular training to maintain muscle mass and insulin sensitivity and to prevent accumulation of fat mass
• Monitor your training with tools that can determine your day to day recovery status and to prevent over training and the accumulation of stress hormones
• Use stress reduction techniques

London nutritionist Steve Hines can design a nutrition and strength training plan to offset the affects of sacropenia.

References

1. Rosenberg, I. H. (1997). Sarcopenia: Origins and Clinical Relevance. J. Nutr. 127 (5): 990S-991S.
2. Hall, D. T. Ma, J. F. Di Marco, S. and Gallouzi I. E. (2011). Inducible nitric oxide synthase (iNOS) in muscle wasting syndrome, sarcopenia, and cachexia. Aging, Vol 3, No 8 , pp 702-715.
3. Haran, P. H. And Rivas, D. A. (2012) Role and potential mechanisms of anabolic resistance in sarcopenia. J Cachexia Sarcopenia Muscle. 3 (3): 157–162.
4. Kershaw, E. and Flier, J. S. (2004). Adipose Tissue as an Endocrine Organ. The Journal of Clinical Endocrinology and Metabolism. 89 (6): 2548-2556.
5. Risbridger, G. P. Bianco, J. J. Ellem, S. J. and McPherson, S. J. (2003). Oestrogens and prostate cancer. Endocrine-Related Cancer. 10: 187–191.
6. Dumond, H. Presle, N. Terlain, B. Mainard, D. Loeuille, D. Netter, P. and Pottie, P. (2003). Evidence for a Key Role of Leptin in Osteoarthritis Arthritis & Rheumatism. 48 (11): 3118–3129.
7. Woodruff, T. J. Carlson, A. Schwartz, J. M. Giudice, L. C. (2008). Proceedings of the Summit on Environmental Challenges to Reproductive Health and Fertility: executive summary. Fertil Steril. 89(2): 281-300.
8. Lee, D.H.  Lee, I. K. Song, K. Steffes, M. Toscano, W. Baker, B. A. Jacobs, D. R  (2006) A Strong Dose-Response Relation Between Serum Concentrations of Persistent Organic Pollutants and Diabetes Results from the National Health and Examination Survey 1999–2002. Diabetes Care. 29 (7). 1638-1644.
9. Stahlhut, R. W. van Wijngaarden, E. Dye, T. D. Cook, S. Swan, S.H. (2007). Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect. 115(6): 876-82.
10. Alonso-Magdalena, P. Morimoto, S. Ripoll, C. Fuentes, E. and Nadal,  A. (2006) The Estrogenic Effect of Bisphenol A Disrupts Pancreatic β-Cell Function In Vivo and Induces Insulin Resistance. Environ Health Perspect, 114 (1): 106–112.
11. Nadal, A., Alonso-Magdalena, P., Soriano, S., Quesada, I., Ropero, A.B. (2009). The pancreatic cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes, Molecular and Cellular Endocrinology. 304(1-2): 63-8.
12. Srikanthan, P. Hevener, A. L. Karlamangla, A. S. (2010). Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III. Sarcopenic obesity and diabetes. 5 (5): e10805.
13. Rasmussen, B. B., Fujita, S., Wolfe, R. R., Mittendorfer, B., Roy, M., Rowe, V. L. and Volpi, E. (2006) Insulin resistance of muscle protein metabolism in aging. FASEB J, 20, 768-9.
14. Robinson, S. Cooper, C and Sayer, A. A. (2012). Nutrition and sarcopenia: A review of the evidence and implications for preventative strategies. Journal of aging research. 510801
15. Marcason, W. (2010). What Is the Effect of a High-Protein Diet on Bone Health?Journal of the American Dietetic Association. 110 (5): 812.
16. Darling, A. L. Millward, D. J. Torgerson, D. J. Hewitt, C. E. and Lanham-New, S. A. (2009). Dietary protein and bone health: a systematic review and meta-analysis. American Journal of Clinical Nutrition. 90: 1674-1692
17. Kerstetter et al (2003). Dietary protein, calcium metabolism, and skeletal homeostasis revisited. Am J Clin Nutr. 78(3 Suppl): 584S-592S.
18. Friedman, A. N. Ogden, L. G. Foster, G. D. Klein, S. Stein, R. Miller, B. Hill, J. O. Brill, C. Bailer, B. Rosenbaum, D. R. Wyatt, H. R. (2012). Comparative Effects of Low-Carbohydrate High-Protein Versus Low-Fat Diets on the Kidney. Clin J Am Soc Nephrol. [Epub ahead of print]