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.