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Sex Matters in Aging. The Canagliflozin Story
* Corresponding author: Warren Ladiges
Mailing address: Department of Comparative Medicine, School
of Medicine, University of Washington, Seattle, WA 98195, USA.
Email: wladiges@uw.edu
Received: 06 September 2022 / Accepted: 09 September 2022 / Published: 30 September 2022
DOI: 10.31491/APT.2022.09.091
Abstract
A promising and novel approach for identifying anti-aging therapeutics has been the repurposing of clinically approved and readily available drugs in mice. Canagliflozin, a clinically approved safe, and effective drug for type 2 diabetic patients, was recently shown to robustly retard age-related lesions in male mice but less so in female mice. While this type of sex disparity is often seen in the field of aging, it does represent a dilemma of not knowing the cause or how translationally relevant the sex differences would be in older humans treated with Canagliflozin. Thoughtful and mechanistic investigations are needed to understand why these differences are present and whether they can be eliminated by new drugs or drug combinations. Success in using repurposed drugs for aging intervention studies in humans will depend on preclinical research to uncover pathways that can be targeted for the benefit of both sexes.
Keywords
Aging intervention, canagliflozin, sex disparities, mouse aging, age-related lesions
Aging is complex and multifaceted. It then follows that
there would be multiple angles to promote prolonged and
resilient healthy aging. One promising and novel approach
has been the repurposing of clinically approved and readily available drugs as diet supplements. To formally assess
the effects of these compounds on evaluating the potential
of extending lifespan, the National Institute on Aging
Intervention Testing Program (ITP) has investigated numerous drugs. Type 2 diabetic (T2D) drugs are one such
category that has been gaining popularity for their use in
delaying aging through managing glucose metabolism and
insulin activity. In a recent publication, Canagliflozin, an
SGLT-2 inhibitor, was shown to retard age-related lesions
in male mice [1]. While impressive, the results represent
the tough but not unexpected dilemma that is often seen
in the field of aging: sex disparities. How large are these
disparities and what does it mean for anti-aging research?
T2D drugs represent a novel therapeutic approach for
aging and have already shown promise in their ability to
mitigate the effects of dementia and reduce the severity
of neurodegenerative diseases [2-5]. Though some drugs
like Acarbose have already been studied at length and
validated in multiple studies [6-8], many drugs are still
being examined. A greater number of validated drugs will
be useful for translational therapies and enhance our ability to manipulate mechanisms and more selectively target
pathways of aging. In the publication, “Canagliflozin
retards age-related lesions in heart, kidney, liver, and
adrenal gland in genetically heterogenous male mice”,
Canagliflozin is shown to have significant differences in
healthy aging for male mice as opposed to female mice
when looking at age-related lesions [1]. Using a validated
geropathology grading platform [6], organs were stained
with hematoxylin and eosin, then graded according to lesion presence or severity. Significant decreases were found
in males in the incidence of adrenal cortical neoplasm and
severity of arteriosclerosis and cardiomyopathy, glomerulonephropathy, hepatic microvesicular lipidosis, and pancreatic atrophy. Females were shown to have significance
only in the severity of pancreatic atrophy, while adrenal
cortical neoplasm and thyroid adenoma trended toward
significance. The breadth of lesions that Canagliflozin was
able to increase resilience to in male mice is as noteworthy as it is puzzling to see such a stark difference in its inability to delay aging pathology in female mice.
Snyder et al. go on to speculate that the reason for the differences in lesion scores between sexes in mice could be
due to either side effects in the female cohort that oppose
the benefits, or that there may be differences in aging-related pathways that account for the ineffectiveness of the
drug [1]. This is not the first-time differences have been
reported for anti-aging drugs. Acarbose, an inhibitor of the
breakdown of complex carbohydrates in the upper digestive tract, also shows sex differences favoring males over
females, including protein ubiquitination, cardiac hypertrophy, and hypothalamic inflammation [7-9]. Although
both drugs target metabolic pathways, they may indirectly
affect other aging pathways such as mTOR signaling [10-11]. Rapamycin, which has been tested at length in mice
and is well validated for its lifespan effects, targets the
mTOR signaling pathway and has significant anti-aging
effects in both male and female mice [12]. It is important
to investigate the pathways involved in sex differences,
which may not only improve our understanding but may
be useful in developing new therapies or drug combination therapies.
To maximize the benefit of the translational research being done, it is important to consider the end user. It is
problematic to ignore the sex differences and proceed to
develop therapies that only work for a specific subset of
the population. With Canagliflozin as a case study, the
best course of action is to work on examining the mechanistic differences to determine how to resolve the failure
of the drug in female mice to extend lifespan or reduce
lesion severity. Due to the significant nature of the differences observed in the paper, it has the potential to be an
excellent starting point for answering this scientific query.
Ultimately, the resolution of these sex differences comes
down to experimentation. Thoughtful and mechanistic
studies need to be completed to understand why these differences are present. Multiple lines of mice could be used
to verify the sex differences and used as a comparison to
narrow down where they originate. RNA sequencing has
proven to be valuable in comparing the transcriptome of
biological cohorts to examine differences in gene expression, especially in aging rodent populations.
Another consideration to unlocking the benefits of T2D
drugs showing sex differences in mice is a multi-targeted
approach. For the increasing number of studies that have
provided evidence of sex differences, there is now interest
in combinations of drugs that target different pathways,
are designed to work better, and have lower hazard ratios
than the individual drugs, even with sex accounted for
[3]. This raises the question of whether the complexity of
aging and the sex differences observed can be mitigated
with combination therapy using drug cocktails. In a recent study, a combination of rapamycin, phenylbutyrate,
and acarbose was able to increase resilience to aging and
reduce the severity of age-related lesions [13]. Though
there were some sex differences in the endpoint assays,
the cocktail was overall better in comparison to any individual drug. It is possible this method could be used to
alleviate the sex inequalities in the case of Canagliflozin
and even enhance the effect seen in males.
In conclusion, Canagliflozin is an excellent case study of
the sex differences challenging T2D drugs for aging intervention approaches. Investigations to help determine the
mechanisms for these differences will help move studies
from mice to humans. Future success using repurposed
T2D drugs will depend on basic research to uncover pathways that can be targeted for the benefit of both sexes.
Declarations
Authors’ contributions
Both authors contributed to the writing of this manuscript.
Availability of data and materials
Not applicable.
Financial support and sponsorship
Supported in part by NIH grant R01 AG057381 (Ladiges, PI).
Conflicts of interest
Warren Ladiges is a member of the Editorial Board of Aging Pathobiology and Therapeutics. The author declares that there are no conflicts.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
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