There is no situation so terrible that it will not be silently accepted as set in stone, only given that it has lasted for long enough to become routine. So it is with aging, and all of the pain, suffering, and death that accompanies it. The present furor surrounding COVID-19 is unusual for casting at least a little light upon the point that infectious disease largely kills older people, and in very large numbers, year in and year out. In the normal course of affairs, no-one cares until it is their turn to be old, frail, and vulnerable.

The immune system decays with age, becoming simultaneously overactive (inflammaging) and incompetent (immunosenescence). It doesn’t just fail at the vital tasks of defending against pathogens and destroying cancerous and senescent cells, but also actively contributes to the onset and progression of inflammatory conditions of aging, from cardiovascular disease to dementia. The principal causes of immune aging are easily described: the thymus atrophies with age, slowing the supply of matured T cells to a trickle by age 50; hematopoietic stem cells responsible for creating immune cells become dysfunctional and damaged; lacking reinforcements, immune cell populations become rife with exhausted, senescent, broken and misconfigured cells.

In the commentary I’ll point out today, the authors point out that mortality due to fungal infections is a particularly neglected aspect of the age-related decline of the immune system. The cost is high, and far too little attention is given to this issue – just as, in the broader picture, far too little attention is given to the issue of immune aging as a whole, and the enormous cost in suffering and death that it causes. Too few programs are attempting to reverse the causes of immune aging, even though this is a realistic goal, with many proof of concept studies in mice achieving positive results over the past few decades. As a species, we prioritize poorly.

Fungal infections in humans: the silent crisis

Humankind has been plagued by infectious diseases throughout history, and the ongoing COVID-19 pandemic is a daunting reminder that this susceptibility persists in our modern society. After all, communicable diseases remain one of the leading causes of death worldwide. Unfortunately, some of these “microbial threats” have been underestimated and neglected by healthcare authorities, although they endanger millions of lives each year all over the world.

Fungal infections (FIs) represent an example of such overlooked emerging diseases, accounting for approximately 1.7 million deaths annually. To put these numbers in perspective, tuberculosis is reported to cause 1.5 million deaths/year and malaria around 405,000 deaths/year. The medical impact of FIs, however, goes far beyond these devastating death rates: FIs affect more than one billion people each year, of which more than 150 million cases account for severe and life-threatening FIs. Importantly, the number of cases continues to constantly rise. Thus, FIs are increasingly becoming a global health problem that is associated with high morbidity and mortality rates as well as with devastating socioeconomic consequences.

A crucial factor that contributes to the rising number of FIs is the drastic increase of the at-risk population that is specifically vulnerable to FIs, including elderly people, critically ill or immunocompromised patients. The overall lifespan increase due to the achievements of modern medicine and social advancements, the growing numbers of cancer, AIDS, and transplantation patients with the concomitant subscription of immune-modulating drugs as well as the excessive antibiotic use compose risk factors and niches for the development of FIs. Furthermore, the increasing usage of medical devices such as catheters or cardiac valves leads to a higher risk for the formation of biofilms. Biofilms represent an assembly of highly diverse, complex and eminently organized cells embedded in an extracellular matrix that conveys protection from physical and/or chemical insults. Thus, biofilms are often resistant to existing treatments and, in fact, are considered to essentially contribute to the high mortality rates associated with invasive FIs.

There is no doubt that the threat imposed by FIs will continue to increase worldwide with a number of obstacles (including resistance development) that need to be overcome. This demands rapid and innovative action at different levels. The search for therapeutic treatment options needs to be intensified. In sum, FIs are crucial contributors to the new old threat of infectious diseases, and upgrading our antifungal armamentarium by improving existing and/or devising novel antifungal strategies remains an urgent medical challenge.