Working on Aging in the Time of COVID-19
As you get older, your are more likely to develop diseases such as cardiovascular disease, neurodegenerative disorders, and cancer. You also become more susceptible to infectious diseases. We have seen the disproportionate impact of COVID-19 on the health of our parents and grandparents.
There are functionally infinite potential permutations of bacteria and viruses. Society can be crippled by new infectious diseases, at their mercy until a vaccine is developed. In the best case scenario it takes 12 to 18 months to develop a vaccine against a new permutation. In the meantime, more people will become infected and many will die.
While no one of any age wants to get COVID-19, the burden is undoubtedly felt the most by the older population. If every age group was as resilient to COVID-19 as those in their 20s and 30s, the virus would not have such a stranglehold on society.
There is no replacement for an effective vaccine. However, therapeutics that slow or reverse aging-related immune system decline may increase the resiliency of older individuals to any immune insult such as to COVID-19 — but also for whatever next infectious disease takes hold.
Aging drugs that improve immune function in older adults may, at minimum, be an interesting stop gap in between the emergence of a new pathogen and the development of a vaccine.
The tl;dr:
- The immune system works less well as you get older.
- This is correlated with increased vulnerability of older individuals to infectious diseases.
- Immune aging “immunosenescence” may be causative as to why older people get sicker from infectious diseases.
- Aging drugs may help older people not get as sick from new infectious diseases.
- We have shown the improvement of immune system function by treatment with some aging drugs in mice.
- We have mixed results of this working in people.
- Immune system function might be an interesting way to test if an aging drug works much more quickly than other healthspan or lifespan makers.
The Numbers: How the Older Fair Worse with COVID-19
As we learn more about COVID-19, we have seen the exponentially worse outcomes for the older and the ill.
The fraction of infected who die from the disease increases exponentially with age. Put simply, older people are much more likely to die from COVID-19. [1]
Of those who contract COVID-19, older individuals are more likely to become sicker. A larger portion of older patients with COVID-19 need to be hospitalized in comparison to younger infected. Resilience to the disease, even if the patient ultimately survives, seems to decrease with age. [1]
Pre-existing conditions increase the likelihood of getting sicker from COVID-19. If you have an age-related disease, regardless of the specific type, you are more likely to get sicker from COVID-19. [3] While it’s currently challenging to understand the potential correlation versus causation here, one theory is that those who have an age-related disease are more likely to be aging faster in all tissues, including the immune system, and therefore be more susceptible to the infection. Put another way, having an age-related disease of any type may be a marker of a patient who is aging ‘quicker’ — not all individuals of the same age are equally healthy. [2]
Targeting Aging to Target Infectious Disease
How do viruses get us sick and why do older individuals get so much sicker from them?
Bio Primer: how a virus makes you sick & how your immune system makes you better
Viruses are tiny protein packages of DNA or RNA. A virus cannot replicate on its own because it lacks the machinery to copy its DNA/RNA and make the protein shell. Therefore, viruses have evolved to be able to spread easily from host to host, enter their cells, and hijack these cells to copy and reassemble multiples of the virus. The host becomes sick from the direct effects of the virus invading and killing cells and from the actions of the host’s immune system as it tries to clear the virus.
A healthy immune system is generally adept at clearing viruses. Various types of immune cells patrol your body, hunting down cells compromised by viruses. Over time, your body also begins to recognize the virus before it infects cells via antibodies. Antibodies are proteins that have very specific heads that bind to other biomolecules. The combination of clearing infected cells and quickly destroying any virus that remains outside the cells is a simplified explanation of how the immune system clears a virus and makes you healthy again. (This is how the antibody tests in development for COVID-19 work — they are looking for the acquired antibodies against COVID-19 that the immune system produces in response to a successful immune clearance).
Innate immunity is the ‘standing army’ that non-specifically protects the body from insults. Adaptive immunity is the immunity to specific pathogens that you gain from a cleared infection or vaccination. Both of these immune system roles function less well in aged individuals.
Why aging makes you more susceptible to infectious disease
The core thesis of the aging field is that underlying healthy cellular and tissue functions break down as we age, and this degeneration is causative in the diseases we associate with aging.
A common metaphor is an old car: the rubber parts of the car all age on a molecular level in a similar way regardless of location, but depending where the part is the aged rubber may manifest as a slipping gear box or a faulty A/C unit. Treating a cracked rubber piece would be equally efficacious in all use-cases, despite a slipping gear box and faulty A/C unit being seemingly unrelated.
Immunosenescence is the progressive decline of the immune system with age. As the immune system ages and loses functionality, the person both is less likely to be able to fight off an infection and less likely to be protected by a vaccine. [3] This is because two key functions of the immune system — the protection of the body during an acute infectious attack (innate immunity) and the development of immunity against previous attacks (adaptive immunity) — are dependent on the generation and activation of specific types of cells. In older populations, the ability of these cells to be generated diminishes and those that do may have mutations or otherwise not function optimally, dampening the immune system’s ability to protect the host.
The immune system isn’t just important for protecting against infectious diseases — it also plays a key role in clearing early cancers and is thought to be relevant to other age related diseases such as neurodegenerative disorders.
Slowing or reversing all-cause aging could improve immune system function — increasing an older person’s ability to fight off infectious diseases.
Susceptibility to infectious disease as a way to test aging drugs
It is challenging to test whether a drug delays aging or increases lifespan in humans. Instead, companies developing drugs for aging must find a classical disease (“indication”) to test their drug in and hopefully show that the drug works.
Susceptibility to infectious disease may be an interesting way to test if a drug slows or improves aging. If we assume that:
- Immune system aging is a primary cause of why aged individuals become sicker from infections, and…
- The selected aging drug improves immune aging, and…
- The immune system improvement occurs relatively soon after dosing with the drug,
an aging drug may reduce the age-relative rate of infections and the proportion of these infections progress into severe sickness, and increase the immune protection from vaccines. As the drug would broadly increase immune function and not be specific to any one virus or bacteria, one effective aging drug should be efficacious across most infectious diseases.
A study from 2009 [4] tested rapamycin’s (a generic human drug which has shown healthspan and lifespan extension in many model organisms) ability to improve immune system function.
This study showed that rapamycin treatment improved the protection of a vaccine against H1N1, presumably by decreasing immunosenescence in the old mouse which allowed it to develop sufficient protection from the vaccine.
This idea was recently tested in people by the biotech company ResTORbio with mixed results. Their lead drug RBT101 is an inhibitor of mTOR, the same target as rapamycin. ResTORbio tested the protective effect of RBT101 against respiratory tract infections, a common infection in older individuals. Their most recent Phase 3 trial did not show any protective benefit of RBT101 against infectious disease. [5]
However, their Phase 2 studies, which used everolimus and BEZ235 (two different drugs from RBT101, both of which also inhibit mTOR) showed a protective benefit of the drug in older individuals against respiratory tract infections and increased immune response to the flu vaccine. [6]
The small amount of data makes it challenging to know if ResTORbio’s Phase 3 study failed because RBT101 didn’t work, because the thesis of aging drugs for immune system function was wrong, or if an operational, patient segmentation, or other unrelated issue confounded the results.
Why do young people die of some infectious diseases?
An aging immune system is not the only reason why people get sick and die from an infection. While COVID-19 has not been shown to be particularly dangerous to most children, many other infectious diseases including the classic flu are especially dangerous to younger individuals. Death rates for the flu show that children under 1 year of age have a fatality rate similar to that of 65 year olds.
The 1918 H1N1 Spanish flu’s death rates were W-shaped — young children, middle-aged adults, and the elderly all were disproportionally impacted by the virus. While no one knows exactly what caused disproportional deaths among young adults to the Spanish flu, one study suggests that the previous H3N8 Russian flu pandemic of 1889 (which young adults would have been exposed to as children) subverted these individual’s immune system and left them more likely to die from the Spanish flu. [7] The H1 strain of the flu was sufficiently different from the H3 strain, leaving young adults uniquely vulnerable. (This is a bit of a confusing concept — here is a TIME article that discusses the paper).
The takeaway from this is that aging is clearly not the only factor that plays into immune system protection against infectious diseases, and these other factors need to be taken into account when contemplating aging drugs for infectious diseases.
Sources
Thanks to Ben Cmejla, Austin Diamond, Taylor Rogalski, and Armand Cognetta for helping me make this sensible.
[1] “Estimates of the severity of coronavirus disease 2019: a model-based analysis” https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930243-7
[2] “Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020” https://www.cdc.gov/mmwr/volumes/69/wr/mm6913e2.htm?s_cid=mm6913e2_x
[3] “Immunosenescence: influenza vaccination and the elderly” http://dx.doi.org/10.1016/j.coi.2014.03.008
[4] “mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells.” https://www.ncbi.nlm.nih.gov/pubmed/19934433
[5] “resTORbio Announces That the Phase 3 PROTECTOR 1 Trial of RTB101 in Clinically Symptomatic Respiratory Illness Did Not Meet the Primary Endpoint” https://ir.restorbio.com/news-releases/news-release-details/restorbio-announces-phase-3-protector-1-trial-rtb101-clinically
[6] “TORC1 inhibition enhances immune function and reduces infections in the elderly” https://stm.sciencemag.org/content/10/449/eaaq1564
[7] “Age-Specific Mortality During the 1918 Influenza Pandemic: Unravelling the Mystery of High Young Adult Mortality” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734171/
