Loss of Muscle Mass with Aging

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 7 No. 2 • April 2004

Loss of Muscle Mass with Aging: Interleukin-6 and Tumor Necrosis Factor-alpha

A recent study1 reports that, in healthy elderly men and women, higher plasma concentrations of the inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were associated with lower muscle mass and lower muscle strength. The authors used baseline data (1997–1998) of the Health, Aging, and Body Composition (Health ABC) Study, which included 3075 black and white men and women aged 70–79 years. With the exception of white men, elderly persons with high levels of IL-6 (more than 1.80 pg/ml) as well as high levels of TNF-alpha (more than 3.20 pg/ml) had smaller muscle area, less appendicular muscle mass (arms and legs), lower knee extensor strength, and lower grip strength. Blacks, who had higher IL-6 and lower TNF-alpha than whites, had greater muscle area and strength compared to whites in both men and women.1

IL-6 and TNF-alpha are proinflammatory cytokines, chemical signals sent and received by the immune system. While cytokines play important roles in initiating and regulating inflammatory processes that protect against infections and induce repair at sites of injury, overproduction of inflammatory cytokines or failure to discontinue inflammation can cause a wide variety of disease conditions, such as arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, cancer, the wasting due to cancer (cachexia), and (as mentioned above) the loss of muscle mass with aging. Chronic administration of TNF-alpha or another cytokine, IL-1, induced weight loss and skeletal muscle wasting in rats.2

Another paper2 reports on a possible mechanism for the muscle wasting with aging reported above. In cell culture and in male C57/bl6 mice, TNF-alpha was shown to inhibit myogenic differentiation by destabilizing the MyoD protein [which plays an important role in cell-cycle exit of differentiating myoblasts (developing muscle cells), muscle-specific gene expression, and myotube (structural elements of muscle cells) formation]. These effects were mediated by NF-kappaB activation, as is seen with oxidative stress and inflammation. Another paper3 reported that transient (as little as 10 minutes) exposure of human myoblasts to TNF-alpha inhibited serum and insulin-like growth factor-1-stimulated protein synthesis. The authors note that the decrease in protein synthesis they observed was similar to the inhibition of protein synthesis seen in skeletal muscle from septic animals.

In a dramatic demonstration of the protective effect of blocking excess TNF-alpha activity in a disease characterized by massive skeletal muscle loss, the anti-TNF-alpha drug Remicade® has been shown to protect dystrophic skeletal muscle from necrosis.4 (The myopathy of Duchenne’s muscular dystrophy is caused by defects in a cell-membrane-associated protein, dystrophin. However, in this study, the blocking of TNF-alpha in a mouse model of the disease showed marked protection against skeletal muscle breakdown, even though it did nothing to correct the dystrophin defects.)

There are many substances that have been reported to reduce inflammation and TNF-alpha levels, including regular exercise,5 acetylcholinesterase inhibitors (in Alzheimer’s disease patients),6 alpha-lipoic acid,7 quercetin,8 N-acetylcysteine,9 nonsteroidal anti-inflammatory drugs,10 estrogen,11,12 and antioxidant vitamins.13 Getting rid of excess fat is also a useful way of reducing TNF-alpha levels, since adipocytes (fat cells) release large amounts of the cytokine.


  1. Visser et al. Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women. J Gerontol 57A(5):M326-32 (2002).
  2. Langden et al. Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization. FASEB J 18:227-36 (2004).
  3. Frost et al. Transient exposure of human myoblasts to tumor necrosis factor-alpha inhibits serum and insulin-like growth factor-1 stimulated protein synthesis. Endocrinol 138(10):4153-9 (1997).
  4. Grounds and Torrisi. Anti-TNF-alpha (Remicade®) therapy protects dystrophic skeletal muscle from necrosis. FASEB J 18:676-82 (2004).
  5. Greiwe et al. Resistance exercise decreases skeletal muscle tumor necrosis factor-alpha in frail elderly humans. FASEB J 15:475-82 (2001).
  6. Lugaresi et al. IL-4 in vitro production is upregulated in Alzheimer’s disease patients treated with acetylcholinesterase inhibitors. Exp Gerontol 39:653-7 (2004). [This paper reports that, in AD patients treated with acetylcholinesterase inhibitors (as compared to untreated AD patients), there was a much higher level of IL-4 (five times higher in unstimulated cultures of peripheral blood mononuclear cells). IL-4 (interleukin-4) is an immunosuppressive cytokine; evidence suggests that it prevents neuronal cell injury. The mechanism may be IL-4 inhibition of interferon gamma and the consequent decrease in the concentration of TNF-alpha and nitric oxide.]
  7. Zhang and Frei. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J 15:2423-32 (2001).
  8. Wang and Mazza. Effects of anthocyanins and other phenolic compounds on the production of tumor necrosis factor-alpha in LPS/IFN-gamma-activated RAW 264.7 macrophages. J Agric Food Chem 50:4183-9 (2002).
  9. Victor et al. N-Acetylcysteine protects mice from lethal endotoxemia by regulating the redox state of immune cells. Free Rad Res 37(9):919-29 (2003).
  10. Joussen et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J (Jan. 30, 2002).
  11. Cenci et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106(10):1229-37 (2000).
  12. Walsh et al. 17-beta-Estradiol reduces tumor necrosis factor-alpha-mediated LDL accumulation in the artery wall. J Lipid Res 40:387-96 (1999).
  13. Vassilakopoulos et al. Antioxidants attenuate the plasma cytokine response to exercise in [untrained] humans. J Appl Physiol 94(3):1025-32 (2003).

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