Open Access | Commentary
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A geropathology approach for identifying therapeutic targets to prevent pathological complications of COVID-19
* Corresponding author: Warren Ladiges
Mailing address: Department of Comparative Medicine, School
of Medicine, University of Washington, Seattle, WA, USA.
E-mail: wladiges@uw.edu
Received: 20 May 2020 / Accepted: 26 May 2020
DOI: 10.31491/APT.2020.06.022
Abstract
Vitally important aspects of dealing with the COVID-19 pandemic include the development of effective treatments for acute illness and prevention of infection. However, severe complications including mortality occur primarily in older adults, so a long-term approach of covering all aspects of infection and disease complications in older people is equally essential in preventing the alarming morbidity and mortality. Since severe pathological consequences of SARS-CoV-2 infection are age-related, a geropathology based platform of identifying agerelated anatomic and molecular lesions aligned with processes of aging will be able to identify multiple targets for combinations of anti-aging drugs. A comprehensive geropathology-driven therapeutic approach of covering complications and vaccine effectiveness by enhancing resilience to aging will therefore play a critical role in preventing the alarming medical complications of disease not only with SARS-CoV-2 but also serve as a model for successfully controlling and preventing future world-wide pandemics.
Keywords
Resilience to aging, COVID-19 complications, SARS-CoV-2 pathology, geropathology
The immediate concern of the COVID-19 pandemic is
that hundreds of thousands of people are being infected
with a virus that appears to mainly attack the respiratory
system so the focus has been on the immune system and
the lungs. It is critical that this be addressed clinically, but
we are suggesting that now is also the time to extend the
scope of investigation to an organismal level and include
all major organs and investigate the pathological consequences of the disease, both short term and long term, as
a way to prevent infection and disease complications. The
SARS-CoV-2 virus has the ability to infect people of all
ages, but severe symptoms and mortality occur primarily in frail older adults who account for the majority of hospitalized patients. Why is this? Currently, in the United
States approximately 80 percent of COVID-19 deaths
have occurred in patients 65 years of age and older, and
fatal outcomes are even more common in patients greater
than 85. Therefore, aging is a major risk factor for developing severe complications related to SARS-CoV-2 infection. An emerging platform for investigating pathological
consequences of age-related disease is geropathology.
Geropathology is defned as the study of the pathology of
aging and considers that all anatomic and molecular lesions within an organ or tissue have a role in aging, not
just those contributing to morbidity and mortality. In other
words, the basic pathobiology of aging affects the functional performance of all organs in the body.
Geropathology is embraced within the field of geroscience, which aims to understand at the cellular and molecular level, interconnections between aging and disease
with a focus on understanding the mechanisms by which
aging contributes to disease as a major risk factor [1]. The
geroscience concept posits that manipulation of aging will simultaneously delay the appearance or severity of major
diseases because they share the same underlying major
risk factor: aging and the multiple pathological processes
involved in aging [2, 3]. The geroscience approach assumes that all diseases that affect primarily older adults
have a common and major underlying cause of declining
function and resilience that is part of the aging process.
This has been established for chronic diseases and is now
a reality for acute infections such as SARS-CoV-2.
In order to answer the question “Why are older people at
greater risk for severe complications of COVID-19?”, we
frst must address the question “How does the geropathology background influence the severity of COVID-19?”
We are dealing with two issues with SARS-CoV-2 infection. The first is acute lung injury (ALI) caused by the
presence of the virus, and the second is the existing presence of anatomic and molecular lesions that will influence
the severity of virus/host-mediated consequences. In preclinical studies in mice, we have an ideal model to address
both questions. There are scoring systems that have been
adapted from human pathology and can be used for determining the severity of ALI in aging mice infected with
SARS-CoV-2. Scoring systems for acute injury in other
organs such as heart and brain are also being adapted for
COVID-19 mouse models. This provides very useful data,
but does not address the question of resilience, ie., resistance to the development of severe pathology and potential death. This is where geropathology assessment can reveal highly informative “background” details by profling
the presence and severity of anatomic and molecular lesions generally associated with increasing age. Anatomic
geropathology profles for aging mice are derived by applying a validated scoring platform to histological lesions
in tissues from major organs [4]. These scores can be used
for correlation analyses with acute tissue injury and other
clinical pathology data. Specifc cell types in lesions can
also be identified using immunohistochemistry and cellspecifc antibody reagents to measure quantitative staining
intensity by digital imaging with programs like QuPath
[5]. Molecular geropathology fngerprints are determined
by DNA sequence analysis of cells identifed in formalin
fxed paraffn embedded tissues with specifc anatomic lesions.
Once the geropathology profiles have been established
and aligned with SARS-C0V-2 infection, it is a matter of
identifying aging processes that match up with the aligned
profiles. Using the aging COVID-19 mouse model, and
qualitative and quantitative platforms such as IHC and
Luminex, tissues can be interrogated for processes of
aging. Some important processes include inflammation,
autophagy impairment, insulin/mitochondrial dysfunction
and oxidative stress, epigenetic dysfunction, and vascular
impairment. This approach is designed to identify aging
processes that increase the risk of developing pathology
with COVID-19. The processes of aging that align with
COVID-19 pathology should be able to be used to define successful intervention of disease manifestation by
showing evidence of cellular homeostasis in concert with
immunological response and decreased geropathology.
The geroscience concept posits that susceptibility to the
pathologic development of COVID-19 complications with
increasing age is not the result of a single aging pathway.
Rather, it is a multifactorial network linked with mechanisms of aging. Therefore, it is a matter of matching the
relevant aging processes with drugs that target specific
molecules mechanistically involved in these processes
and administering these drugs in a manner informed by
the data. A number of drugs have been shown to have
antiaging effects not only in preclinical studies but also in
clinical investigations. Most of these are already clinically
approved for other diseases such as diabetes and examples
include metformin, rapamycin, acarbose, as well as others. Since the development of COVID-19 pathology is
age-related, and multiple processes are involved in aging, there will not be one single drug that will prevent
COVID-19 complications in the elderly. Rather, it will
require combining anti-aging drugs that fit parts of the
geropathology profle into combinations that target all the
parts. Drug combinations that result in improvements in
multiple aspects of healthy aging significantly delay the
appearance of pathology and frailty [6]. In other words,
there is increased resilience to aging that is more characteristic of a younger biological age compared to an older
chronological age.
The real question then is “Is a more youthful biological
state beneficial for alleviating pathology and fatal outcomes of COVID-19 infection in older people?” The ultimate expectation is that processes of aging gravitate towards a functional homeostasis representative of a young
age and align more with the expected youthful biological
profle. Observations from data generated on specifc processes of aging are critical to show that a geropathology
approach for alleviating severe COVID-19-related pathology is possible, and increases the validity of properly
matched combinations of anti-aging drugs for enhancing
and protecting elderly people from the devastating effects
of SARS-CoV-2 infection. These predictions are not unreasonable or risky expectations, because drug combinations are designed to target processes of aging based on
mechanistic targets of each individual drug.
There are several challenges with a geropathology driven
treatment/prevention approach. The first is not knowing
exactly when a drug combination should be administered
to older people. Whether these types of drugs would be
complimentary to other treatments at the time of illness
is not known but preclinical studies could easily address
this. Whether and how to treat with a drug combination
before clinical illness or exposure to the virus is a very
relevant question. Preclinical studies in aging mice pretreated with drug combinations for three months show
delayed aging (Ladiges, et al., unpublished observations).
Three mouse months is equivalent to 7 to 8 human years,
which is a considerable duration for older people, but
shorter prophylactic treatment times will most likely be effective. Preclinical and clinical studies could easily address this. Another related question is how to identify older people at risk for complications of COVID-19. Since
severe COVID-19 pathology is an age-related condition,
we can pose the question in a different way by asking who
is resilient to physical aging thereby identifying people
that, by defnition, would be more resistant to COVID-19
complications. Stress tests are already being developed for
resilience to aging, so there are potential clinical applications for this approach. Another related challenge is how
will a combination of anti-aging drugs affect older people
already taking one or more drugs for specifc medical conditions. In fact, many older people are polypharmacy patients, ie., they are taking fve or more drugs. Aside from
the fact that the anti-aging drug combination may alleviate the need for some, or all medically indicated drugs,
there are ethical and clinical issues that would need to be
addressed. A third challenge is determining if an antiaging drug combination would enhance the effectiveness
of a SARS-CoV-2 vaccine. Although a vaccine has not yet
been developed for widespread clinical use, this is a very
relevant question, since it is known that immune responsiveness to vaccines generally decreases with increasing
age, and some anti-aging drugs can enhance immune responses.
In summary, effective treatments for acute SARS-CoV-2
illness and prevention of infection are vitally necessary
aspects of dealing with this pandemic. However, a long
term geropathology approach of covering all aspects of
infection and disease complications in older people is
equally essential in preventing the alarming morbidity and
mortality of not only the COVID-19 pandemic but also
for future world-wide pandemics. Therapeutic targeting of
aging processes has the potential of enhancing resilience
to aging and subsequently age-related diseases including
infectious disease agents thereby improving and extending
healthy living with increasing age.
Declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Acknowledgements
No funding was received for the authoring of this commentary.
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