It is widely appreciated that old people have a poor time of it when it comes to infectious disease. Seasonal influenza kills tens of thousands of older people every year in the US alone. The aged immune system functions poorly, and vaccinations for many conditions have low success rates in older people. Thus the vast majority of COVID-19 deaths are old people exhibiting immunosenescence. Given that the world at large seems to be entirely accepting of the yearly toll of influenza, while COVID-19 is classed as an apocalypse of some sort, one has to wonder how much of the hysteria surrounding COVID-19 stems from the rare – but highly publicized – deaths of younger individuals. Or perhaps if the rising toll of every influenza season was reported in the same way as deaths from COVID-19, more might be done? Human psychology is a strange thing.

An enormous amount of government and other funding will be directed towards fundamental infectious disease research in the years ahead, once things have settled down somewhat and COVID-19 has faded into the backdrop. That is is one consequence of a pandemic that captures the attention of the world to the degree that this one has, deservedly or otherwise. This was perhaps the perfect storm, as ominous rumblings and awareness initiatives have been ongoing for some time regarding the threat of SARS-like viruses making the leap from animals to humans. A critical mass was finally reached. That COVID-19 has so far turned out to be less terrible than suspected at the outset is beside the point. The organizations of the world were primed to react in the way they are now to the first SARS-like virus that appeared remotely threatening.

The prospect of a large increase in funding for infectious disease and immunology research means that scientists in every relevant field of study are racing to position themselves to try to capture a portion of those funds. We outsiders don’t see the ferocious pace of grant writing, but published papers are a visible sign of this energetic process. A few recent examples are noted below. Researchers involved in immunology and aging are taking this moment in history to remind the world that, yes, the immune system decays with age, old people bear the brunt of infectious disease as a result, and perhaps we should do something about this, now that we can target the mechanisms of aging – the cause of immunosenescence.

Covid-19 and Immunity in Aging Populations – A New Research Agenda

As we age, health conditions associated with aging, particularly noncommunicable diseases such as heart disease, cancers, and metabolic and autoimmune diseases, combined with treatments for these diseases and with immune senescence, substantially affect responses to vaccines and infectious diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as the receptor for SARS-CoV-2, the virus that causes Covid-19, and it has been suggested that differential levels of ACE2 in the cardiac and pulmonary tissues of younger versus older adults may be at least partially responsible for the spectrum of disease virulence observed among patients with Covid-19.

Even as the brunt of severe illness from Covid-19 is being borne by aging adults, we are navigating partially blind in efforts to develop vaccines and therapies to stop this and future pandemics, since we lack knowledge of the mechanisms of immunity to protect this population. If we can delineate principles of effective immunity in the elderly, we might also be able to develop new strategies for broader disease prevention and control in older populations.

COVID-19 is an emergent disease of aging

Here, we found that the case fatality rate for COVID-19 grows exponentially with age in Italy, Spain, South Korea, and China, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to therapeutic approaches that affect specific pathways, by approaches that target the aging process.

Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence).

Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: (i) the presence of subclinical systemic inflammation without overt disease, (ii) a blunted acquired immune system and type I interferon response due to the chronic inflammation; (iii) the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and (iv) accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state.