An evolutionary perspective…on

immunometabolism.
( from A.Wang, R.Medzhitov)

Summary :

This article explores the connection between metabolism, immune responses, and organismal
physiology from an evolutionary perspective. It discusses the role of metabolic programs in
controlling organismal life history programs, particularly in the context of immune response to
infection. The article also highlights the importance of understanding the interplay between
metabolic programs and immune responses in maintaining organismal health. It further
discusses the potential therapeutic implications of targeting metabolism in immune-related
diseases.

1. How do different metabolic pathways contribute to immune responses during infection?

2. What are the cellular equivalents of organismal life history programs, and how do they relate
to metabolism?
3. How can an evolutionary perspective help us understand metabolic and inflammatory
disorders such as diabetes and obesity?

What is the life history theory?

Life history theory, described in the 1950s by biologists, is an evolutionary framework that seeks
to explain the diversity of life strategies observed in different species. It focuses on allocating
limited resources to different life history traits, such as growth, reproduction, and
maintenance, in response to environmental challenges.

According to life history theory, organisms must effectively distribute their finite resources
to optimize their reproductive success under environmental constraints. Favourable
environments, characterized by abundant resources, promote investment in growth and
reproduction. In contrast, unfavourable environments, including resource scarcity or insults
such as pathogens or toxins, shift resource allocation towards maintenance and survival
strategies.

This theory recognizes that organisms face trade-offs in resource allocation, as investing more
resources in one trait may come at the expense of others. For example, allocating more
resources to growth and reproduction may reduce the resources available for maintenance and
defence against environmental stressors.

Life history theory has been applied to various aspects of biology, including studying metabolic
and inflammatory disorders. By understanding how organisms allocate resources in different
environments, researchers can gain insights into the underlying mechanisms and potential
interventions for these disorders.
What are the three biological programs: maintenance,
growth and reproduction?
Maintenance, growth, and reproduction are three fundamental life history programs organisms
allocate resources to optimize their reproductive success in different environments.

Maintenance refers to allocating resources towards processes that ensure the survival and well-
being of the organism. This includes mechanisms involved in stress resistance, tissue protection,
and defence against environmental insults such as pathogens and toxins. Maintenance
programs are generally associated with catabolic metabolism and energy conservation.

Growth involves the allocation of resources towards the increase in size, mass, and complexity
of an organism. It encompasses processes such as cell division, tissue development, and organ
formation. Growth programs are associated with anabolic metabolism and energy-consuming
processes.

Reproduction refers to the allocation of resources towards the production of offspring. It

includes processes such as gamete production, mating, and parental care. Reproduction
programs are also associated with anabolic metabolism and energy consumption.

These life history programs are not mutually exclusive, and organisms must balance their
allocation of resources to optimize their fitness in different environments. The specific
allocation of resources to maintenance, growth, and reproduction depends on the quality of
the environment and the availability of resources.

Each program
functions at the
organismal and
cellular level.

What are the Organismal and Cellular life history

programs?
Cellular life history programs refer to allocating resources within individual cells to different
processes, such as growth, reproduction, and maintenance, in response to environmental
conditions. These programs are regulated by various signalling and transcriptional pathways.

Organismal life history programs, on the other hand, encompass the allocation of resources at
the whole-organism level to growth, reproduction, and maintenance. These programs are
regulated by complex physiological systems, including the growth hormone-insulin-like growth
factor (GH-IGF), hypothalamic-pituitary-gonadal (HPG), and hypothalamic-pituitary-adrenal
(HPA) axes.

Environmental cues and resource availability influence both cellular and organismal life history
programs. Favourable environments promote investment in growth and reproduction, while
unfavourable environments shift resource allocation towards maintenance and survival
strategies.
These life history programs play a crucial role in shaping the phenotype and fitness of
organisms, as they determine how resources are allocated to different biological processes to
maximize reproductive success in specific environmental conditions such as nutritional scarcity
or infection ( insults).

Two types of the same Maintenance programs:

Defense (Immunity) and Dormancy ( Resilience).
Nutrient scarcity.
Regarding nutrient scarcity, metabolic programs, signalling pathways, and metabolic pathways
work together to optimize resource allocation and survival strategies per life history theory.

During nutrient scarcity, organisms activate catabolic metabolic programs to conserve

energy and rely on alternative fuel sources. This involves breaking stored energy sources, such
as fat reserves, through lipolysis and beta-oxidation. These catabolic programs are regulated by
signalling pathways such as AMP-activated protein kinase (AMPK), which senses cellular energy
status and promotes energy-conserving processes.

In addition to metabolic programs, nutrient scarcity activates signalling pathways in stress

response and maintenance. For example, the signal transducer and activator of the
transcription 3 (STAT3) pathway plays a role in promoting cell survival and tissue protection.
STAT3 signalling can regulate various metabolic pathways, including autophagy, a cellular
process that degrades and recycles damaged or unnecessary cellular components to provide
energy and building blocks.

Furthermore, nutrient scarcity can induce metabolic pathways such as fatty acid oxidation
(FAO), which allows cells to utilize fatty acids as an energy source when glucose availability is
limited. Various metabolic enzymes and transcription factors regulate FAO, and its activation
helps to maintain energy homeostasis during nutrient scarcity.

These metabolic programs, signalling pathways, and metabolic pathways are all part of the
maintenance program within the life history theory framework. During nutrient scarcity,
organisms prioritize maintenance and survival over growth and reproduction, and these
programs work together to ensure the survival and well-being of the organism in challenging
environments.

How do cells deal with infection? What are the life history
programs involved?
When cells encounter infection, they activate specific life history programs to mount an effective
immune response. These programs involve both defence and dormancy strategies
(maintenance programs).

The defence program is an anabolic life history program that the immune system activates in
response to infectious agents. It involves activating inflammatory mediators and mobilising
resources to support immune cell proliferation and the synthesis of defence molecules, such as
cytokines and antimicrobial proteins. This program relies on anabolic metabolism, including
glucose and glutamine utilization, to fuel the energy-demanding processes of immune cell
activation and proliferation.

“While both growth/proliferation and defence rely on anabolic programs, they have distinct
features and are controlled by different signalling and transcriptional programs (in this example,
c-Myc versusHIF1α).” TLR signals induced by LPS in macrophages actively suppress catabolic
programs. LPS stimulation inhibits AMPK, a key activator of catabolic metabolism, and up-
regulates iNOS and NO production. NO nitrosylates proteins in the mitochondrial electron
transport chain, leading to suppression of oxidative phosphorylation (OXPHOS). This
suppression of OXPHOS helps to redirect cellular resources away from catabolic pathways and
towards anabolic pathways, which is essential for the immune response.

On the other hand, the dormancy program is a catabolic life history program induced by the
immune system in response to infection to assure tissue protection from pathogens and
inflammatory damage (tolerance to infection). This program is associated with resource scarcity
and involves suppressing non-essential functions, such as growth and reproduction, to conserve
energy and promote stress resilience. Dormancy programs rely on catabolic metabolism, such
as fatty acid metabolism, to provide energy and support stress resistance.

When the body is under inflammatory stress (e.g. viral infection), the hypothalamic-pituitary-
adrenal (HPA) axis is activated. This axis is responsible for releasing hormones that promote
catabolic (breakdown) processes in the body. TNF, a cytokine released during inflammation,
also promotes lipolysis, the breakdown of fat cells, and reduces glucose utilization in skeletal
muscle and adipose tissue. This helps to redirect energy resources away from growth and
reproduction and towards tissue protection.

In addition to these catabolic processes, the body also shifts to using alternative fuels such as
ketone bodies during inflammation. Ketones are produced by the liver from fatty acids and can
be used by the brain and other tissues for energy. Ketones have been shown to have direct
cytoprotective effects, primarily by reducing oxidative damage. They can also signal to regulate
inflammation negatively.

On a cellular level, hematopoietic stem cells (HSCs) shift their metabolic programs to OXPHOS
and fatty acid metabolism in response to oxidative stress. This helps to improve their survival.

The engagement of catabolic/maintenance programs has been observed to confer stress

resistance in a variety of settings, such as calorie restriction, ischemic preconditioning, and
therapeutic hypothermia. These findings suggest that these programs may play a role in tissue
protection during inflammation and other forms of stress.

The activation of these life history programs during infection is regulated by various signalling
and transcriptional pathways. For example, the defence program is regulated by signalling
pathways such as the nuclear factor-kappa B (NF-κB) pathway, which is activated by
inflammatory mediators and promotes the expression of immune response genes. The
dormancy program, on the other hand, is regulated by signalling pathways such as the activated
protein kinase (AMPK) pathway, which senses cellular energy status and promotes energy-
conserving processes.
Overall, cells deal with infection by activating specific life history programs, including defence
and dormancy, to mount an immune response and ensure survival in the face of infectious
agents.

NF-Kb

hypothalamic–pituitary–adrenal (HPA) axis, Glucose ( Glc), Glucocorticoids (GC), Fatty Acids (FA), Triglycerides (TG)

“The evolutionary perspective described above provides a new framework for the
conceptualization and study of how metabolic programs support organismal, tissue, and cellular
processes in changing, and not always welcoming, environments. The application of life history
theory is particularly informative because it describes the logic of how resources are allocated
between growth, reproduction, and maintenance programs as a function of environmental quality.
We suggest here that maintenance can be divided into two metabolically distinct programs: the
energy-preserving, catabolic dormancy programs and the energy-consuming anabolic defence
programs. Importantly, this life history theory perspective can effectively be applied within the
lifespan of an individual organism and an individual cell to examine how each entity adapts to its
ever-changing environment.” Wang A.
Depending on the environment, metabolites made up in cells (reduced or oxidized molecules,
ROS, growth factors, etc.) can trigger metabolic programs (anabolic the energy-consuming or
catabolic the energy-preserving), which in turn lead to different life history programs (growth,
proliferation, or maintenance). When we apply these concepts to the immune system, then it
comes the chart below :
Environment Life history programs Outputs /conditions