A new study examining thousands of patients who suffer from a particularly crippling form of arthritis, and take a certain type of drug for treatment, has yielded several important conclusions. One is that the extremely successful category of drugs known as TNF inhibitors (TNFi) significantly reduces Alzheimer’s disease in these patients. The other is that an important cause of aging—inflammaging—appears to be treatable.
Twenty years ago, the gerontologist Claudio Franceschi combined the words inflammation and aging to refer to a phenomenon now seen as one of the most important breakthroughs in the quest to reverse the aging process. The result—the birth of inflammaging—spawned a new field of study that has revealed many truths about the impact of inflammation on aging bodies.
Previously, scientists recognized inflammation as the essential immune system response to infections and injuries. When you get a fever or swelling, that’s your immune system working to keep you healthy. Without the ability to launch an inflammatory response, a common cold or minor injury could kill you.
Most young peoples’ immune systems are constantly poised to mount a rapid and powerful inflammatory counterattack against infections and injuries. This is the good side of inflammation.
That same hair-trigger immune response in older adults, however, may turn into a liability. When the body launches an immune attack on itself—mistaking its own cells for infectious pathogens or injuries—an overactive immune system can be as lethal as an underactive one. This is the basis for autoimmune diseases.
Inflammaging extends autoimmunity even further—recognizing it as a major aging accelerator.
Is That Really Me?
The reason may simply be a case of mistaken identity. If you’re older, you may have had one of those “Is that me?” moments when you see a picture of yourself that differs significantly from the more youthful image you were accustomed to.
Our immune systems appear to have a similar problem—and they can interpret the impacts of age as an infection or injury. In response to a perceived threat, our bodies send out signaling proteins to recruit other immune system resources. The most important appears to be tumor necrosis factor (TNF). TNF got that name fifty years ago, long before its functions began to be unraveled. Despite the fact that this moniker is now considered inaccurate, the name stuck. (See Tumor necrosis factor: is it time to change the name?, Arthritis Research & Therapy, 2014.)
The Many Faces of TNF
TNF does many things—and sometimes at cross purposes. For example, it might activate repair processes in cells while simultaneously commanding them to die, generating chronic, low-grade inflammation at the heart of the vicious cycle of inflammaging.
Relatively recently, scientists discovered that decreasing the amount of TNF in the body creates significant therapeutic value. In 2020, the anti-TNF drug Humira passed $165.8 billion USD in total cumulative sales. With that TNF advancement, Humira became the most successful drug—and TNF-inhibitors the most lucrative drug class—in history.
Despite their expense and potentially severe side effects, TNF alpha inhibitors are FDA-approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and several other diseases.
As research expands, age-related changes in TNF alpha appear to be responsible for accelerated aging—inflammaging. TNF is also linked to atherothrombosis, cardiovascular disease, obesity, type 2 diabetes, and insulin resistance. (1, 2)
Despite the evidence, TNF inhibitors have not been widely tested on those conditions due to high costs and risk profiles. To reduce costs and risks, researchers are aggressively seeking small molecule TNF inhibitors that can be synthesized, instead of the more costly option of growing inhibitors in bioreactors.
A major problem with TNFi biologics is a potential to provoke their own immune system reactions—including infections, malignancies, increased heart failure rate, drug-induced lupus, demyelinating disorders, and skin reactions. Small molecule drugs, on the other hand, may have fewer side effects. Small molecules may also be able to cross the blood brain barrier more easily and treat central nervous system disorders.
TNF Inhibitors Protective Against Dementia
A recent paper speaks to the many benefits of anti-inflammaging, specifically for people who suffer with ankylosing spondylitis (AS) and are treated with TNF inhibitors. These patients have significantly lower rates of dementia than AS patients not treated with TNF inhibitors.
This large-scale population-based study recruited 4,082 AS patients and 20,397 age- and gender-matched subjects as controls. Of the AS patients, 1,208 (29.6%) were treated with TNF inhibitors for a mean duration treatment of 180.46 months and a median duration of 49 months.
The AS patients treated with TNFi were significantly less likely to develop Alzheimer’s. (Adjusted odds ratio 0.76 [95%CI 0.56–1.02). These findings bolster similar results from other studies, which showed that exposure to anti-TNF agents reduce the risk of developing Alzheimer’s in rheumatoid arthritis patients.
The authors conclude that “ITNF-α seems to play a major role in the pathophysiology of AD. There is molecular evidence that elevated TNF-α levels may enhance Aβ production and decrease its clearance, leading to neuronal loss and cell death, and resulting in cognitive decline.”
We, from the Reboot Your Age program, find this extremely promising for two reasons. One is the research that we expect will produce superior anti-TNF drugs. The other reason is that there are already many therapies known to reduce inflammation and lower inflammaging.
There are far too many to list and explain here, which is why we have produced the Reboot Your Age program and app to automate the process of living younger for longer. To get you started on your own Reboot journey, we’ve put together a list of activities that will help you ward off cognitive decline.
1. TNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging, Blood 2019
2. Human aging is associated with altered TNF-α production during hyperglycemia and hyperinsulinemia, Endocrinology and Metabolism, 2001
Ankylosing spondylitis (AS) is a chronic progressive and debilitating form of arthritis with associated extra-articular features including uveitis, intestinal and lung apical inflammation and psoriasis. Putative associations between AS and neurologic disorders has been relatively overlooked. The purpose of this study is to assess the link between AS and major neurologic disorders and whether treatment with Tumor-Necrosis-Factor inhibitors (TNFi) has an impact on that association.
A retrospective cross-sectional study was carried out based on the Clalit Health Services (CHS) computerized database. AS patients were compared to age- and gender-matched controls with respect to the proportion of Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and multiple sclerosis (MS). The impact of AS therapy (biologic vs conventional therapy) was assessed as well.
4082 AS patients and 20,397 age- and gender-matched controls were identified. AS was associated with a higher prevalence of AD (odds-ratio(OR) 1.46 [95%Confidence-interval(CI) 1.13–1.87], p = 0.003), epilepsy (OR 2.33 [95%CI 1.75–3.09] p < 0.0001) and PD (OR 2.75 [95%CI 2.04–3.72], p < 0.0001), whereas no statistically significant association was found for MS. Association with PD remained significant in the multivariate analysis (OR 1.49 [95%CI 1.05–2.13],p = 0.027). Within AS patients, the use of TNFi (OR 0.10 [95%CI 0.01–0.74], p = 0.024) were associated with a lowered risk of developing AD.
AS is positively associated with AD, PD, and epilepsy but not MS. AS patients treated with TNFi have lower rates of AD.