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The GIST

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THE GIST

  • Could people with diseases like long COVID and chronic fatigue syndrome (ME/CFS) be aging more rapidly than normal? Recently, a large review paper made that case in long COVID (and referred to ME/CFS).
  • The authors demonstrated that processes associated with aging such as chronic inflammation, immunosenescence (exhausted T-cells), dysbiosis, mitochondrial dysfunction, cellular senescence, and metabolic dysregulation have all shown up in long COVID (as well as ME/CFS). Similar problems have shown up over time in people with exposed to another infectious stressor – people with HIV.
  • The first anti-aging treatments they focused on were involved in, what else, on tamping down chronic inflammation – likely a key issue in long COVID, ME/CFS, and many chronic diseases. They proposed a variety of treatments (etanercept, prostaglandin EP2 receptor antagonism agents, and NLRP3 inflammasome inhibitors (MCC950 (also known as CRID3 or CP-456,773), OLT1177 (Dapansutrile), CY-09, Inflamazome’s compounds.) some of which are being trialed in long COVID.
  • With regard to diet, they focused on reductions in butyrate producing bacteria in the gut. Reductions of these gut protective bacteria have been linked to literally dozens of chronic illnesses and a breakthrough in finding ways to repopulate the gut with these crucial bacteria (or to increase gut butyrate levels) would be beneficial indeed.
  • With regard to mitochondrial rejuvenation, the authors pointed to NAD+ and/or its precursors to combat NAD+ declines seen in aging. They reported that NAD+ declines are “a salient feature” of ME/CFS.  They also proposed trying out urolithin-A – a   metabolite that’s been shown to improve mitochondria functioning, clean out old and inflamed mitochondria, reduce neuroinflammation, reverse cognitive decline, improve muscle functioning, and prolong life spans in laboratory animals.
  • They pointed to a class of drugs we haven’t heard of before – senotherapeutic or senolytic drugs that clean out old, moldering cells that just won’t die and are pumping out inflammatory factors. Getting rid of these cells is a main focus of the longevity movement and the authors illuminated dozens of potential treatments including hyperbaric oxygen treatments that appear to be able to do this.
  • In the last treatment section they focused on metformin and Rapamycin – which have been able to increase lifespans in animals, reduce inflammation, and increase gut diversity (metformin), help with T-cell exhaustion (Rapamycin), restore autophagy (both) and others.
  • The authors ended by describing long COVID as a disease in which homeostasis – the ability to maintain biological stability – is under attack. The authors refer to this ability to snap back as resilience or “physiological reserve”, which wanes as we age. Simply put, the body lacks the ability to recover completely from, in the case of long COVID and many people with ME/CFS, an infection.  ME/CFS has been described in a similar way numerous times over the years.
  • While it’s a bit wrenching to think that, on top of all the other stuff going on in these diseases, one might also be biologically aging more rapidly, the good news in all this is that the longevity, or geroscience, field is booming with billions of dollars of research funding going into it every year.
  • If diseases like ME/CFS and long COVID are causing accelerated aging people with these diseases might very well benefit from the interest in aging research and the new treatment options that are sure to follow.
Could people with diseases like long COVID and chronic fatigue syndrome (ME/CFS) be aging more rapidly than normal? Even if I don’t particularly like the idea that I am biologically going down the tubes a bit faster than others, it fits with my experience. I still vividly remember 30 years ago watching some quite elderly ladies passing me chattering away as I struggled to make my way down a walking path. The dissonance was glaring.

Recently, a large review paper made the case that the biological process of aging has accelerated in long COVID. The paper, “Long COVID as a Disease of Accelerated Biological Aging: An Opportunity to Translate Geroscience Interventions Accelerated Biological Aging in Long COVID“, was produced by an interesting blend of Saudi Arabian, Egyptian, and U.S. researchers from the Mayo Clinic and Northwestern University.

A New Focus?

Epigenetic modifications

Epigenetic modifications build up over time. Could the epigenetic clocks in ME/CFS and long COVID be sped up?

The authors asserted that long-COVID researchers should focus on fundamental processes associated with aging that have shown up in long COVID such as chronic inflammation/immunosenescence, dysbiosis, mitochondrial dysfunction, cellular senescence, and metabolic dysregulation. (How interesting that both ME/CFS and long-COVID research is already naturally trending in many of these directions.)

Interestingly, the first instance of accelerated aging the authors pointed to was a post-viral one: HIV. About 15 years ago, HIV researchers began picking up signs that HIV survivors were aging more rapidly than normal. This showed up in an increased incidence of disorders associated with aging, and biological evidence.

Their epigenetic “clocks”, for instance, appeared to be sped up. (Epigenetics refers to changes that alter the expression of our genes over time. The longer we are alive, the more epigenetic changes that occur.) They also exhibit increased markers of innate immune-driven inflammation and immune dysregulation linked to aging. Increased levels of exhausted T-cells, problems with natural killer cells, dysbiosis (gut flora dysregulation), mitochondrial dysfunction – all of which have been found in ME/CFS –  and are also associated with aging – have shown up prematurely in HIV patients.

Referring at times to ME/CFS studies, authors spent over 20 pages detailing what they believe are signs of increased biological aging in long COVID. They included:

increased levels of exhausted CD8+ T cells, latent herpesvirus reactivation, a hyper-immune response to those viruses (leading to T-cell exhaustion), dysregulation of B-cells, elevations of the chemokine eotaxin (CCL11), microglial activation (neuroinflammation), brain and neuronal injury (increased tau proteins and neurofilament light chain (NFL)), gut microbiome dysregulation, leaky gut, mitochondrial dysfunction including impaired fatty acid metabolism (perhaps produced by herpesvirus activation), a shift toward anaerobic metabolism, DNA damage, reduced telomere length, and others

Potential Treatments

The authors of the paper outlined several treatment areas they believe show promise in turning back the clock, so to speak.

Anti-Inflammatory Agents

The first anti-aging treatments focused, what else, on tamping down chronic inflammation – likely a key issue in long COVID, ME/CFS, and many chronic diseases.

They proposed assessing treatments used to treat cardiovascular diseases (canakinumab and colchicine) and anti-inflammatory treatments that have been shown to extend lifespan in mice such as etanercept, prostaglandin EP2 receptor antagonism agents, and NLRP3 inflammasome inhibitors (MCC950 (also known as CRID3 or CP-456,773), OLT1177 (Dapansutrile), CY-09, Inflamazome’s compounds.

The good news is that inflammation has been identified as potentially a key mover in long COVID and many anti-inflammatory clinical trials (dexamethasone, plasma exchange, plasmapheresis, intravenous immunoglobulin (IVIG), RSLV-132, baricitinib, anakinra (IL-1β receptor antagonist), sirolimus, deupirfenidone, complement pathway inhibitors (ROCUNEST, Zilucoplan are currently underway in long COVID)).

From Skeptic to Advocate: Wes Ely, Long COVID, ME/CFS and his Big Baricitinib Trial

Diet

Given the link between gut flora (microbiome) problems and inflammation, it was no surprise to see dietary manipulations make the list of possible anti-aging therapies. The gut is often given short shrift in these diseases, but the evidence of its importance to chronic diseases continues to pile up.

A huge 2024 type 2 diabetes gut study, which involved 10 prediabetes and diabetes cohorts in three countries (yes, diabetes has a lot of funding!), concluded that changes in the gut came first and set the stage for type 2 diabetes. The lead author stated, “Therefore, we are confident that the observed changes in the gut microbiome happen first and that diabetes develops later, not the other way around.”

The reduction of butyrate-producing bacteria in type II diabetes could not have been a surprise given the similar reductions found in other diseases including (take a seat…) Gulf War Illness (GWI), fibromyalgia, and ME/CFS, inflammatory bowel disease (IBD), Crohn’s disease, ulcerative colitis, irritable bowel syndrome (IBS), colorectal cancer, hypertension, metabolic syndrome, Type I and II diabetes, multiple sclerosis, rheumatoid arthritis, Sjogren’s Syndrome, systemic lupus erythematosus, atherosclerosis, stroke, Parkinson’s disease, Alzheimer’s disease, and others.

Eventually, I gave up – every chronic disease I looked at featured reduced levels of butyrate producing bacteria. Butyrate reductions are such a common element of chronic illness that one must assume that efforts are underway to find ways to boost them. Dozens of clinical trials are underway.

The authors noted that the gut is receiving its due in long COVID and that probiotics, larazotide acetate (a gut permeability regulator), and fecal transplant trials are all currently underway.

Mitochondria Rejuvenation

The authors pointed to the partial success of AXA1125 in improving Chalder Fatigue scores in long COVID, but it’s clear that, while AXA1125 may help, much more is needed in this direction. The suggestions regarding mitochondrial rejuvenation were surprisingly sparse but interesting.

AXA1125 – A New Mitochondrial Enhancer Is Being Trialed in Long COVID

The authors pointed to NAD+ and/or its precursors (nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)) supplementation to combat NAD+ declines seen in aging, and reported that NAD+ declines are “a salient feature” of ME/CFS. Nicotinamide riboside helped remove damaged mitochondria, reduce tau protein levels, and improve neuroplasticity in the brains of a mouse model of Alzheimer’s.

Urolithin-A is a really interesting metabolite produced by the (uh oh) gut bacteria. It’s been shown to improve mitochondria functioning, clean out old and inflamed mitochondria, reduce neuroinflammation, reverse cognitive decline, improve muscle functioning, and prolong live span in laboratory animals.

A recent study found that urolithin-A was able to reduce inflammation and improve the clean-up processes in the brains of an Alzheimer’s mouse model. A blog on urolithin-A is coming up.

That was it for mitochondrial rejuvenation.

Bye-Bye Zombie Cells – the Senotherapeutics Option

Zombie cells

Zombie cells hang around past their normal lifespan, emitting pro-inflammatory substances. Senotheraputics treatments aim to get rid of them.

As we age, we tend to accumulate more and more senescent, mostly non-functioning cells (aka “Zombie cells”) that emit inflammatory factors, break down the “extracellular matrix” (connective tissue!), contribute to telomere degradation (a sign of aging found in ME/CFS), and contribute to osteoporosis.

Finding ways to clean out these cells and reduce inflammation has become a major focus of anti-aging therapies, and senolytic, or senotherapeutic, treatments are being trialed in a wide variety of disease.

Osteoporosis is, of course, a major concern in chronic diseases like ME/CFS and FM which primarily affect women and make exercise difficult. A recent Mayo study suggested the researchers are on track to help out at least some women with osteoporosis employing a cancer drug called dasatinib and quercetin, which produced increased bone growth but only at 2 and 4 weeks. It worked best on women with high rates of senescent cells.

Studies suggest that fisetin, a flavonoid polyphenol, navitoclax (ABT-263), famotidine (a mast cell inhibitor), suramin, CXA-10, BMS-986301, epigallocatechin gallate (EGGG), tucatinib, anti-diabetic drugs (acarbose, SGLT-2 inhibitors), new anti-obesity medications (GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP agonists (e.g., tirzepatide, lixisenatide) can all help remove senescent cells. Interestingly, hyperbaric oxygen therapy (HBOT) is a possibility as well.

Rapamycin/Rapalogs and Metformin – Enhancing Autophagy and other Processes

Autophagy is another garbage clearing process, but in contrast to cells, it refers to cellular components. If damaged organelles – in particular, the mitochondria – are not cleared out, the cell will suffer.

Metformin has been shown in some studies to increase lifespan and protect against age-related disorders probably through its ability to improve autophagy and thus reduce inflammation. It also appears to be able to increase gut diversity, and, interestingly, reduce the risk of long COVID.

Rapamycin’s ability to extend the lifespan in several animal models helped to jumpstart the longevity field. Rapamycin’s ability to do that appears to rest in on its ability to reduce the number of exhausted T-cells (a clear problem in ME/CFS), tone down MTORC1 activation, increase gut diversity, reduce inflammation and enhance autophagy. Resveratrol, spermidine and again fisetin may also be able to enhance autophagy.

A Rapamycin ME/CFS trial is underway under the auspices of the Simmaron Research Foundation.

Simmaron’s ME/CFS Trial of Rapamycin – a Mitochondrial Enhancer – to Begin Soon

Signs of Accelerated Aging in ME/CFS

Some studies have explicitly stated finding signs of accelerated aging in ME/CFS. A 2018 CDC study found evidence of teleomere reduction that translated to roughly 10.1–20.5, 4.0–8.2 and 6.6–13.7 years of additional aging depending on the degree of ME/CFS (full, almost ME/CFS, fatigued). Back in 2013, Dr. Newton stated that she felt the ME/CFS could benefit from studying aging processes. Dr. Klimas recently reported that the T-cells in ME/CFS patients look like they’ve aged 16 years. A muscle study proposed that the muscles in people with ME/CFS had prematurely aged. The title of one paper “Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis” said it all about the possibility that the blood vessels in ME/CFS are aging. Fatigue in older adults was associated with basal ganglia dysfunction – which is found in ME/CFS and probably FM as well.

Are “Old” Muscles Holding People with Chronic Fatigue Syndrome (ME/CFS) Down? Plus Tompkins’ Team Promises New Insights

The Homeostatic Diseases

The authors ended by describing long COVID as a disease in which homeostasis – the ability to maintain biological stability – is under attack. When the body is in homeostasis, the system responds to a stressor – and may bend under the strain – but then snaps back to normality.

The authors refer to this ability to snap back as resilience or “physiological reserve”, which wanes as we age. Simply put, the body lacks the ability to recover completely from, in the case of long COVID and many people with ME/CFS, an infection. Something that happens during the infection impairs “the biological mechanisms of resilience”.

While aging could be described as a disease of disrupted homeostasis on virtually every level, ME/CFS, too, has been viewed as a disease of impaired homeostasis. Nancy Klimas has been the foremost champion of the idea that a stressor (usually an infection) has pushed ME/CFS patients into an alternate steady state from which it’s difficult to escape. The idea, though, goes way back.

In 1994, Gray and Martinovic proposed that problems with fatty acid metabolism caused “many homeostatic system(s) (to) become deranged in ME/CFS and held in that state by minor stressors.” Niblett (2007) proposed that “urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.”

Gupta’s 2009 model proposed that stress to the HPA axis had forced it into an “alternate steady state” that prevented it from returning to homeostasis. Reuter echoed Gray and Marinovic when in 2011 he proposed that “carnitine homeostasis” was disturbed.

Barnden moved the homeostasis idea to the brain in 2011 when he proposed that an “insult to the midbrain” which “affects multiple feedback control loops” “disrupt(ed) local central nervous system homeostasis“.

Nancy Klimas’s group’s 2014 paper, “A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War Illness and chronic fatigue syndrome”, proposed that men with ME/CFS were in an “alternative steady state” characterized by hypercortisolism, low testosterone, and a shift towards a Th1 immune response. Women, on the other hand, were caught in an “alternate homeostatic state” characterized by hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation.

In 2018, Germain and Maureen Hanson found “a disturbance in homeostasis of metabolic networks“. In 2022, they noted that the “numerous altered pathways” present depended on glutamate metabolism, which they called “a crucial component of the homeostasis of many organs in the body”. In 2023, Marks used the “central homeostasis network” in the brain to propose that the “dyshomeostasis” in ME/CFS and long COVID is “caused by a chronic state of multisystemic disequilibrium including endocrinological, immunological, and/or metabolic changes.”

Note how often the metabolism and the stress response figure in these hypotheses.

The Upside – Turning Back the Biological Clock in ME/CFS, Long COVID and Allied Diseases?

The Geroscience Hypothesis

The Geroscience Hypothesis from Shafqat et Al.

While it’s a bit wrenching to think that, on top of all the other stuff going on in these diseases, one might also be biologically aging more rapidly, the good news in all this is that the longevity, or geroscience, field is booming.

The “Interventions Testing Program (ITP)” at the National Institute of Health (NIH) is dedicated to identifying the treatments that extend the health and lifespan of mice, and should be explored further. (While mice are not humans, note that mice studies are often the entryway to human trials.)

Thus far, the ITP has identified dozens of interventions that might be able to turn back one’s biological clock. Included are some familiar (rapamycin, fish oil, resveratrol, nicotinamide riboside (NR), methylene blue) ones as well as many I’ve never heard of.

Billions of dollars are going to fund longevity research every year. If diseases like ME/CFS and long COVID exhibit accelerated biological aging, they should benefit from the increasing interest in longevity. Three billion dollars, for instance, has been invested in a company focused on cellular regeneration called Altos Labs. Altos Labs’s explanation of its work sounds like it might relate to a disease characterized by low resilience and difficulty responding to stress.

“Cells in healthy, resilient states resist stressors that give rise to disease, but this diminishes with aging. Early experiments have shown that this ability to resist stressors can be restored.”

It was nice to see a long journal article dedicated to explicating the similarities between aging, ME/CFS and long COVID, and potentially providing some new treatment options such as some immunotherapies and senotherapeutics. We don’t know if diseases like ME/CFS and long COVID are causing accelerated aging, but if so, they stand to benefit from the interest in aging research.

Health Rising’s Quickie Summer Drive Update

target piggy

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This is Health Rising’s first blog on longevity research but with that field exploding and with so many biological similarities between aging and ME/CFS, long COVID and allied diseases showing up it won’t be last. We’re committed to keeping on top of all possibilites.

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