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Targeting metabolism through exercise and nutrition to rejuvenate an aging immune system
* Corresponding author: Brandt Pence
Mailing address: 304 Elma Roane Fieldhouse, 495 Zach H Curlin
St, Memphis, TN 38152, USA.
Email: bdpence@memphis.edu
Received: 06 September 2022 / Accepted: 09 September 2022 / Published: 30 September 2022
DOI: 10.31491/APT.2022.09.088
Abstract
Dysregulated metabolism is a hallmark of the aging process. Immune function is tightly controlled by cellular metabolism, and emerging evidence indicates that aged immune cells have alterations in metabolism that may promote aging-related disease. Lifestyle interventions including diet and exercise are potent strategies for targeting metabolic dysfunction in aging, but to date, only a few studies have examined the ability of exercise or diet to regulate immunometabolism, despite their well-known positive effects on healthspan and lifespan. Utilizing lifestyle modification as precision medicine to target age-related diseases through modulating immunometabolism is promising, but a great deal of work remains.
Keywords
Immunometabolism, exercise, diet, inflammaging, immunosenescence
Advancing age has long been associated with declining
immunity, but the recent (and ongoing) COVID-19 pandemic has brought this to the attention of many outside the
relatively small fields of biogerontology and geroscience.
Aging impairs immune responses (broadly termed immunosenescence) and increases chronic inflammation (colloquially referred to as inflammaging) through a variety of
mechanisms that have been reviewed in detail recently [1].
Various geroprotector drugs, especially mTOR inhibitors
[2], have shown some promise in enhancing immunity
in older adults. Nevertheless, well-validated therapeutic
strategies for boosting immune responses during aging
remain elusive. Lifestyle interventions such as physical
exercise and dietary modification have received considerable attention as therapies to promote healthspan and
lifespan, due in no small part to their multifaceted health
benefits, low cost, and strong safety profile compared to
many pharmaceuticals. To a large extent, these strategies
are eustressors that affect cellular and systemic metabolism. Aging profoundly dysregulates human metabolism
[3], so many of the benefits of diet and exercise are likely
to derive from their metabolic effects.
In recent years, it has become clear that cellular metabolic
programs drive the phenotype and function of immune
cells. While initial observations were made over half of
a century ago [4], the rapid expansion in laboratories
studying immune cell metabolism in the last two decades
has led to an explosion in research in what is now termed
immunometabolism. Immune cell metabolism is highly
complicated and has been comprehensively reviewed elsewhere [4, 5], but in general, pro-inflammatory activation
of immune cells such as T cells and macrophages is associated with activation of glycolysis, the pentose phosphate
pathway, and fatty acid synthesis, while anti-inflammatory
and pro-memory responses are supported by fatty acid
oxidation and mitochondrial metabolism. Dysregulation
of immunometabolism is, by extension, associated with a
host of chronic diseases including age-associated diseases
such as cardiovascular disease and cancer [5]. While immunometabolism is understudied in the context of aging,
there has been some progress in this area in the last several years. In general, aged monocytes and macrophages
have been observed to have reduced mitochondrial respiration and defective NAD+
metabolism, and this is associated with increased inflammation [6]. Conversely, aged
T cells have increased mitochondrial respiration, likely
due to increases in the proportions of memory cells, and
aging also dysregulates metabolic reprogramming during
activation in T cells [7]. Strategies to normalize immunometabolism during aging may therefore have substantial
utility as treatments for age-related chronic and infectious
diseases.
In recent years, a variety of nutritional strategies have been popularized which have been shown to improve
health- and/or lifespan, at least in model organisms. For
the most part, these are based either on some form of
short-term fasting (e.g., intermittent fasting, time-restricted feeding) or alterations in dietary macronutrient content.
Low carbohydrate ketogenic diets (KDs) are the most
prominent example of the latter, and dietary interventions
currently have the best evidence supporting a dietary effect on immunometabolism. KD or supplementation with
the ketone β-hydroxybutyrate suppresses inflammasome
and monocyte activation during coronavirus infection
in aged mice [8], and there is a significant body of work
indicating that ketones alter cellular metabolic pathways
associated with inflammation, including by suppressing
glycolytic activation [9]. In addition to KD, other dietary
strategies including intermittent fasting and amino acid
restriction have anti-inflammatory effects [10], suggesting
that dietary changes may be simple interventions that are
efficacious in altering immunometabolism and capable of
being used in a precision medicine context.
While physical exercise is well known as a driver of
metabolic changes in skeletal muscle, heart, and other
tissues, to date there is very little published research on
its effects on immunometabolism. Long-term moderate
aerobic exercise training is generally anti-inflammatory,
at least when undertaken by individuals with low-grade
inflammatory conditions (including aging) [11]. So far,
the limited attempts to characterize metabolism in circulating immune cells have found few changes pre- vs. postexercise, whether this is interrogated after a single exercise bout [12] or after a training intervention [13, 14].
However, exercise redistributes immune cells, thereby
shifting their circulating proportions, and most exercise
studies to date have examined heterogeneous peripheral
blood mononuclear cell populations. This introduces a
substantial likelihood of biasing results by measuring different cell populations before and after exercise. Some
indirect evidence, primarily from gene expression studies,
does suggest that exercise training could increase mitochondrial metabolism in circulating immune cells [11]. So
far, though, this has not been conclusively demonstrated
directly, and it remains to be demonstrated that exerciseinduced immunometabolic changes are linked to the antiinflammatory effects of regular exercise training.
To summarize, aging results in a multifaceted decline of
immune function that promotes (chronic and infectious)
disease susceptibility and systemic inflammation. Metabolic reprogramming drives phenotypic and functional
changes in immune cells, and there is now emerging
evidence that aging alters immunometabolism in ways
that may cause immunosenescence and inflammaging. As
inexpensive and effective strategies to target metabolism,
physical exercise and dietary interventions hold tremendous promise for ameliorating aging-related diseases
through immunometabolic reprogramming. While there is
some published support for this, especially in the context
of dietary interventions, substantially more work is needed to demonstrate that exercise and/or diet can be used to
target immunometabolism for precision medicine.
Declarations
Authors’ contributions
Brandt D. Pence developed the concept for the editorial and wrote the manuscript.
Availability of data and materials
Not applicable.
Conflicts of interest
Brandt D. Pence is an Associate Editor of Aging Pathobiology and Therapeutics. He declares no other conflicts of interest and was not involved in the journal’s review or decisions related to this manuscript.
Ethical approval and consent to participate
Not applicable.
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