TNFα Blockade Prevents Sarcopenia and Increases Life Span in Mice

Today's open access research reports a sizable effect on sarcopenia in aged mice via blockade of TNFα, an inflammatory signal molecule associated with cellular senescence and generated by senescent cells. Sarcopenia is the progressive loss of muscle mass and strength that takes place with age, more severely in some individuals than in others, but everyone is affected. The drug used in the study is Etanercept, already widely employed to treat autoimmune conditions. It functions as a decoy receptor, binding circulating TNFα to prevent it from interacting with cell receptors to trigger detrimental changes in cell behavior. The outcome of note is that treated mice maintain muscle volume from 12 to 22 months of age, while controls lose ~20% of muscle volume over the same period.

Etanercept is not a drug that one would take for the long term on a whim. Like most existing approaches to suppressing immune overactivation in autoimmune conditions, it is a blunt tool. It suppresses immune signaling and activity across the board, both necessary and inappropriate, and the side effects thus include a potentially dangerous weakening of the immune response to infection. In this case the drug is a tool for the purposes of research, not a potential treatment. It is used to produce what looks a lot like a confirmation of the role of senescent cell accumulation and consequent chronic inflammatory signaling in the onset of sarcopenia with age. One possible way to remove a sizable portion of the harmful TNFα signaling, without disrupting the beneficial TNFα signaling, is to get rid of senescent cells.

Senescent cells accumulate with age, lingering where they should be destroyed, either by programmed cell death or by the immune system. These errant cells generate the senescence-associated secretory phenotype (SASP), a mix of inflammatory, pro-growth, and other signals. When sustained over the long term, the SASP is very disruptive of tissue and immune function, a sizable contributing factor in age-related degeneration. TNFα features prominently in the SASP, so while that connection isn't called out in this paper, it seems likely that one could use senolytic therapies that selectively destroy senescent cells in order to prevent sarcopenia.

Pharmacological blockade of TNFα prevents sarcopenia and prolongs survival in aging mice

Aging is accompanied by chronic low-grade inflammation ("inflammaging"), which could have a causal role in sarcopenia. Tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-10, and interleukin-15 might contribute to the loss of muscle mass. TNFα is a particularly interesting candidate, being a non-redundant target in inflammatory human diseases associated to complex multi-cytokine inflammatory responses. In addition, TNFα is known to promote muscle wasting and cachexia by promoting protein degradation while decreasing protein synthesis and by inhibiting muscle regeneration by blocking proliferation and differentiation of muscle stem cells. In aged muscle, this inhibition seems to be preferentially mediated by TNFα released by bone marrow-derived leukocytes and TNFα genetic knockdown protects against aging-induced fiber loss and reduction of stem cell regenerative capacity. TNFα also promotes apoptosis of both type I and type II muscle fibers.

Etanercept is a dimeric fusion protein that acts as soluble receptor interfering with TNFα binding to tissue receptors and has been employed for the treatment of autoimmune diseases for over two decades, with excellent efficacy and safety profiles. We evaluated the effects of TNFα blockade on spontaneous aging in wild type mice aged 16 to 28 months (corresponding to 50-90 years of human age). This treatment quenched age-associated spontaneous muscle loss, reduced fiber type shift, improved muscle function, and modestly increased animal life span.

We found that spontaneous aging in mice reflects many features of human aging at the skeletal muscle level. Specifically, we observed that between 12 and 28 months of age, corresponding to 40-90 years of age in humans, aging mice lost weight and muscle mass. This was accompanied by progressive reduction of fiber cross-sectional area and of mouse endurance during exercise. Fiber size decline from 12 to 22 months was severe and further worsened at 28 months. Accordingly, MRI-measured muscle volume and body weight decreased starting from month 22 of age. The cells of innate and acquired immunity were consistently detectable in skeletal muscle at 22 months of age and remained stable thereafter. The concentration of circulating cytokines followed comparable kinetics. This suggests that inflammation could start early in aged mice, reaching a "steady state" at a low level for an extended period.

Comments

Are there other ways in which the immune system becomes more inflammatory with age outside of senescent cells? Dysregulation of T regulatory cells with age?

Posted by: jimofoz at December 15th, 2020 4:33 PM

TNF alpha might be elevated in sarcopenia as a defense mechanism for viral infection.

The more I look the more I find virus and microbial burden are associated with any age related disease you pick.

"Synergistic anti-HSV effect of tumor necrosis factor alpha and interferon gamma in human corneal fibroblasts is associated with interferon beta induction"
https://www.sciencedirect.com/science/article/abs/pii/016635429390083U

"Patients with inflammatory rheumatic diseases treated with tumor necrosis factor (TNF) inhibitors have up to a 75% increased risk for herpes zoster infection, compared with those treated with traditional disease-modifying antirheumatic drugs (DMARDs), researchers reported here at the European League Against Rheumatism Congress 2012.
"https://www.medscape.com/viewarticle/765594

"Synergistic anti-HSV effect of tumor necrosis factor alpha and interferon gamma in human corneal fibroblasts is associated with interferon beta induction"

https://www.sciencedirect.com/science/article/abs/pii/016635429390083U

Posted by: Lee at December 16th, 2020 5:42 AM

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