Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people

Abstract

SUMMARYAgeing is associated with low-grade inflammation and markers such as IL-6 possess prognostic value. Tumour necrosis-alpha (TNF-a ) initiates the inflammatory cascade and has been linked to several ageassociated disorders. It remains, however, unknown if TNF-a is associated with mortality in old populations. The aim of the present study was to investigate if serum levels of TNF-a were associated with all-cause mortality independently of interleukin (IL)-6 in a prospective study of 333 relatively healthy 80-year-old people. A Cox regression model was used to explore effects of TNF-a and IL-6 on survival in the following 6 years. A total of 133 participants died during this follow-up period. TNF-a was associated with mortality in men, but not in women, whereas low-grade elevations in IL-6 were associated strongly with mortality in both sexes. TNF-a explained only 7% of the variability in IL-6 and effects of the two cytokines were independent of each other as well as of other traditional risk factors for death [smoking, blood pressure, physical exercise, total cholesterol, co-morbidity, body mass index (BMI) and intake of anti-inflammatory drugs]. These findings indicate that at least in old populations chronic elevated levels of TNF-a and IL-6 have different biological functions that trigger age-associated pathology and cause mortality.

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

“…Based on the well-documented increase in circulating TNF-α levels with aging [6][7][8][9][10][11][12][13] and increases in apoptosis of myonuclei in aged skeletal muscles, [18,19,22], we examined whether apoptotic signaling via the extrinsic pathway contributed to sarcopenia. Our data show that pro-and anti-apoptotic proteins in the extrinsic apoptotic pathway are affected by aging in fast (plantaris) and slow (soleus) skeletal muscles of rats.…”

“…In humans, serum levels of catabolic cytokines, such as TNF-α [7,9,12] and IL-6 [6,11,32], are increased in healthy elderly compared to young adults. Serum concentrations of TNF-α have been proposed as a prognostic marker of all cause-mortality in centenarians [7] and with age-associated pathology and mortality in 80-year old adults [9]. Several studies have also drawn associations between the increases in circulating cytokines and the sarcopenic process [11,13].…”

“…Although this phenomenon is well documented in animal and human studies, the underlying mechanisms leading to sarcopenia remain to be fully elucidated. The contributing mechanism(s) leading to sarcopenia are multi-factorial and may include: denervation and reinnervation of motor units, especially within skeletal muscles composed of a high degree of type II muscle fibers [1][2][3]; an alteration in the hormonal milieu in which anabolic hormone concentrations progressively decline [4,5]; elevated concentrations of inflammatory mediators that are not only associated with disease states, but also occur in healthy older adults [6][7][8][9][10][11][12][13]; and myonuclear loss through apoptotic mechanisms [14][15][16][17][18][19].…”

Fatigue in older adults: an early indicator of the aging process?

“…An evolving definition of inflammation in gerontology is low-grade activation of the innate immune system, leading to chronic production of inflammatory mediators. Inflammatory processes in general have been implicated as predictors of or contributors to chronic diseases and conditions of aging (117), such as cardiovascular disease (118), low cognitive performance (119), osteoarthritis and dementia (120), frailty (121,122), muscle wasting (123), physical performance (123,124), disability (125,126) and mortality (127)(128)(129). These associations have been…”

Impaired hypertrophy in myoblasts is improved with testosterone administration

“…The C2 cells displayed slower and diminished differentiation profiles compared to the C2C12 cells and were also more susceptible to TNF-α-induced inhibition of differentiation and induction of apoptosis [27]. Because muscle wasting is associated with reduced muscle mass [28,29] and increased susceptibility to TNF-induced muscle protein degradation [30][31][32], this comparative model provided us with an excellent representation of muscle atrophy, hypertrophy and adaptability, thus, enabling the determination of potential regulators associated with muscle wasting. The second model utilised C2C12 cells that had undergone multiple population doublings (PD) vs. parental SUBMITTED VERSION ONLY-There will be errors in this manuscript version in comparison with the final published version available in J Steriod Biochem Mol Bol at: Link.…”