Rejuvenation of Immune Function is One of the More Important Outcomes to Engineer through the Treatment of Aging

One would hope that it does not require an ongoing pandemic and related hysteria to point out that old people have poorly functioning immune systems, and thus suffer disproportionately the burden of infectious disease. But perhaps it does. The 2017-2018 seasonal influenza, a modestly more severe occurrence of something that happens every year, killed something like 60,000 people in the US alone, with little notice or comment. There is nothing so terrible that it won't be accepted - ignored, even - if it is normal.

Floodgates of funding for infectious disease research and development have been opened in response to COVID-19, and while no doubt all too little of it will be spent wisely or usefully (public funding being the very definition of waste and corruption) it has certainly prompted many groups to try to position themselves to benefit. Those who have, all along, been working on ways to try to make older people more resilient via improvement in their immune function are perhaps more deserving than others, but it really isn't the case that much of this work is closer than five to ten years away from practical realization and completed human trials.

Of the ways to restore immune function in the old, the worst are the small molecule drugs that show signs of adjusting metabolism in the right direction. For example, the mTOR inhibitors that just failed a phase III trial for reducing influenza incidence in the old. Better drug or drug-like approaches are those that target regrowth of the atrophied thymus. The thymus is where T cells of the adaptive immune system mature, and the production rate is reduced to a trickle in the old - a major cause of immune aging. In humans, there is data for the growth hormone approach of Intervene Immune, and better data for sex steroid ablation, to restore the production of T cells.

Further, regeneration of lymph nodes, vital to coordination of an immune response, and regeneration of the hematopoietic stem cell population that creates all immune cells will be beneficial - but existing approaches to these challenges are by no means close to readiness for clinical trials. Selective destruction of malfunctioning, senescent, and exhausted immune cells is also likely to be beneficial - but only removal of senescent cells via senolytic therapies is a very near term prospect at the present.

At the end of the day, therapies capable of making a 70 year old exhibit the immune profile and response of a 40 year old would be transformative. The world has come to accept that sizable numbers of older people die from infectious disease every year, and that this is set in stone and little can be done about it. That is simply not the case - a great deal can be done about it. It just requires the will and funding to move ahead with the most plausible programs of immune rejuvenation.

It is worth noting that the pandemic statistics referenced in today's open access paper require some interpretation and none should be taken either at face value or as usefully applicable across the board. Context is everything. Testing for COVID-19 is presently very selective for symptomatic, more severe cases. No-one yet has a good grasp on how many mild cases there are, and that is everything for determining actual mortality risk. Further, circumstances such as an enclosed cruise liner are not representative of the way matters progress in the broader population. And so on.

Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections

Aging is a complex, multifactorial process that leads to loss of function and is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Although there is still much debate in the scientific community, proposals have been made to classify aging as a disease in order to develop therapeutic strategies to prevent or delay the onset of age-related illnesses. Increasing frailty with age leads to an increased risk of many diseases. These diseases are commonly referred to as age-related. Many pathogens are more infectious and prevalent in the elderly, and may be referred to as gerophilic (from Greek, géros "old man" and philia, "love"). Some infections, including COVID-19, are not exclusively gerophilic, as younger people may also become infected. However, these individuals have mild symptoms or remain asymptomatic, while the elderly experience substantially more severe symptoms and lethality. The term gerolavic (from Greek, géros "old man", and epilavís, "harmful") may more appropriately describe infections that cause the most harm in the elderly.

Statistics from the COVID-19 pandemic indicate that COVID-19 is a gerolavic infection, one that disproportionately affects the elderly. According to Worldometers, an online resource aggregating data on COVID-19, of the 139,580 people infected worldwide as of March 13, 2020, 70,733 patients had recovered and 5,120 had died. Based on these data, the mortality rates (number of deaths/number of cases), or the probability of dying if infected by the virus, were determined to be 3.6% for individuals aged 60-69, 8% for individuals aged 70-79, and 14.8% for patients aged 80 years or older. The majority of the infected population are 50 and older, while the majority of the deceased are 60 and older.

An open coronavirus analysis project provides further insight into the mortality rates of COVID-19, specifically using data from the Diamond Princess Cruise, where all passengers were exposed to SARS-CoV-2 for an extended period. Of the approximately 1,690 passengers over 65 years of age, 7 passengers died, suggesting a death rate of 0.41%. This death rate is approximately 4.3 times higher than that of influenza. As more countries start reporting statistics, these death rates are likely to be adjusted. These statistics indicate that the infectivity of SARS-CoV-2, and the severity and lethality of COVID-19, are age-related.

One of the possible causes of the age-associated increases in COVID-19 infection rate, severity, and lethality is immunosenescence. Immunosenescence is a well-known age-related process contributing to the global burden of disease. Among the factors contributing to immunosenescence is the chronic involution of the thymus with increased age. Indeed, the infection rates of COVID-19, separated by age, are correlated with involution of the thymus. The thymus gland is most active early in life, reaching maximum size within the first year. Its activity then declines with age until an individual reaches 40 to 50, after which there are negligible traces of the thymus remaining, replaced by fibrotic tissue. As a result of thymic involution, the number of naïve T cells exiting the thymus decreases significantly, with substantial declines in older age.

Age-associated immunosenescence leads to a reduced ability to resist infection, while infection produces biological damage and loss of homeostasis. This ultimately contributes to accelerated aging and the development of age-related diseases, and further accelerates immunosenescence. In support of this model, infections and other age-related diseases are among the main causes of death in the developed world and in developing countries.

Due to the gerolavic nature of COVID-19, the classical preventative measures and treatment strategies used for targeting infectious diseases may not be as effective, and there is a need for alternative geroprotective and senoremediative strategies. Here we compare the expected benefit of treatments for elderly populations (60 years and older) that are currently in development, including standard preventative strategies such as vaccines and antivirals targeting SARS-CoV-2, and the potential added benefit of speculative geroprotective strategies such as rapalogs, NAD+ boosters, senolytics, and stem cell treatment. These additional measures may be used in isolation or as adjuvant therapies to reduce infection risk, symptom severity, or improve vaccine efficacy.

Therefore, interventions that enable immunocompromised elderly to mount an immune response to newly developed vaccines are necessary to help eradicate the disease and reduce the associated mortality. To avoid substantial loss of life and quality of life, primarily among the elderly and vulnerable populations, governments and healthcare systems should investigate preventative and intervention strategies stemming from recent advances in aging research. As discussed in this paper, small clinical studies have shown that several geroprotective and senoremediative interventions, such as treatment with sirolimus and rapalogs, can induce immunopotentiation, increase resistance to infection, and reduce disease severity in the elderly, without severe side effects.

Many of these predicted geroprotectors are available as supplements; however, no meta-analysis or metaclinical trials have been performed at scale to evaluate their effectiveness. The COVID-19 pandemic highlights the paucity of clinical trials on the effects of dietary supplements and drugs on aging and immunosenescence. The existence of pseudoscience and anecdotal promotion in the supplement industry does not mean that protective compounds do not exist. Dietary supplement vendors and pharmaceutical companies need to actively engage in preclinical and clinical research to evaluate the effectiveness of the currently available products on immunosenescence and aging.

Comments

There's a practical way for people reading this blog to contribute to aging science. There is a petition over at Change.org signed by Aubrey de Grey asking the World Health Organization to release comprehensive data on covid-19 patients. The data is to be studied to determine genetic causes of immunosuppression among the elderly. Just search for Aubrey de Grey on the site. It will take 2 minutes.

Posted by: Morpheus at April 6th, 2020 2:22 PM

Excellent! Signed it and how easy it was to do.

Posted by: Morpheus at April 6th, 2020 9:32 PM

@Nico: Agreed 100%.
Regardless of Covid's true case fatality rate, no epidemic in the past apart from the Spanish flu saw hospitals overwhelmed and morgues closed for capacity. But this is where we are at now in spite of a lockdown that has undoubtedly interrupted corona's exponential transmission. Can you imagine what the situation would be without restrictions?

For the life of me i can't figure how some people can't see it. Just over the last 3 weeks Covid killed 15000 people in Italy, which correspond to 85000 in the US given the difference in population size.

So I repeat, more people than what America's most recent severe flu killed in one year were wiped out in only 3 weeks... and after restrictions had been in place for one week already... and in fact in a much smaller area than the whole of Italy, which means that if the outbreak had been allowed to spread unchecked throughout the country (like the flu in the US was) now we would be looking at around five times that figure. In US terms this would translate to 412000 casualties in just a few weeks. This isn't some abstract mathematical modelling based on guesses but a very matter-of-fact extrapolation from real data (i.e. dead bodies).

And if some Covid patients may have died of other pathologies with the virus being only a contributing or confounding factor (doubtful since we are talking about a true prevalence that is at the absolute most 10%), Covid deaths are hugely unreported because people who don't die in hospital never get tested and in the first days of the epidemic some weren't diagnosed even if they did die there.

As a case (or cases) in point:
- There is a town in Italy that in March 2019 registered 24 deaths while the number was 145 last month, with only 30 of these certified as Covid deaths. So even pretending that none of these 30 people who had Covid was killed by Covid, what did these additional 91 people (4 times the usual number) die of?
- Then there's another town that in March 2019 counted 45 deaths, while last month it buried 135, only 20 of which were tested for Covid. So again: even pretending that none of these 20 people who had Covid was killed by Covid, what did these additional 70 people (almost twice the usual number) die of?
- Then there is another town where in March 2019 only 2 people died but last month the number was a staggering 45, of which only 11 were tested for Covid. So one last time: even pretending that none of these 11 people who had Covid was killed by Covid, what did these extra 32 people (a staggering 16 fold increase) die of?

https://www.agi.it/cronaca/news/2020-03-29/coronavirus-giorgio-gori-lombardia-morti-ufficiali-7961437/

This was the pattern in Lombardy in March 2020 but it is now happening everywhere the virus was allowed to spread next.

Forget speculations about transmission rate and case fatality: just count the
coffins. Even without having any idea about what the body inside of them died of, the sheer excess in the number of graves dug says it all.
We are all upset at the negative consequences that the pandemic will bring to anti-aging research in the short term, but pretending that the situation isn't what it is doesn't really help anyone.

Posted by: Barbara T. at April 6th, 2020 11:46 PM

@Nico: I'm not sure Reason was directly comparing Covid-19 to influenza. His main point seemed to be that 'normal' ways that cause thousands (and millions) to die prematurely are overlooked by the media and human beings in general. This is true of smoking, alcohol use, obesity and air pollution. All massive killers yr after yr.

Posted by: Steven B at April 7th, 2020 12:57 AM

@Nico: The flu in Spain last year had a mortality rate of 0.76% (830,000 infected, 6,300 deceased).

Posted by: Antonio at April 7th, 2020 1:36 AM

@Steven B: Covid is 100% involuntary and unwanted - people don't choose it like they do with cigarettes, booze, and bad diets. Huge difference. So media reaction can't possibly be the same.

Posted by: Barbara T. at April 7th, 2020 2:21 AM

Signed both petitions, I bet DRACO would have no problem getting crowdfunded this time.

Posted by: Corbin at April 7th, 2020 9:59 AM

Why do you post these "press release / pr studies" by Alex Zhavoronkov?

This is not new science

He's just pumping his company's (In-Silico) tools which have yet to produce anything of major value

Posted by: donald dagle at April 7th, 2020 10:36 AM

I signed it also, plus sent to others I know.

Posted by: Robert at April 7th, 2020 3:43 PM

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