When T Cells Run Out of Fuel: How Stress, Metabolism, and Aging Shape Our Immune Defenses

A new review in Trends in Endocrinology & Metabolism (Shangguan et al., 2025) explores why our immune soldiers — CD8+ T cells — so often falter under pressure. Whether fighting chronic infections, tumors, or simply aging with us, these frontline defenders can lose their edge. Scientists call this exhaustion or senescence, but at the root lies something more fundamental: bioenergetic stress and substrate scarcity.

The study’s thesis: metabolism and epigenetics are inseparable

The paper shows that when T cells are activated, they switch fuel systems:

• Glycolysis (fast-burning glucose metabolism) powers rapid attack, expansion, and inflammation.

• Oxidative phosphorylation (OXPHOS) (slower mitochondrial metabolism) sustains long-term memory and balance.

But hostile environments — tumors, chronic infections, or the aged body — starve T cells of oxygen, glucose, amino acids, and cofactors. The result? Mitochondria falter, and without the right metabolites (acetyl-CoA, SAM, NAD+, α-KG), T cells can’t maintain the epigenetic programs that define their identity. They slip into exhaustion or senescence: still alive, but functionally paralyzed.

Mapping this onto the ERM / Stress Adaptation framework

In the Exposure-Related Malnutrition (ERM) model, the body adapts to stress by reallocating energy and nutrients. Short-term, this is protective. Long-term, it leads to trade-offs and depletion.

1. Acute Response (Fueling the Fight)

   • T cells ramp up glycolysis to mount a strong, inflammatory attack.

   • Substrate demand spikes: glucose, amino acids, fatty acids.

2. Adaptation (Switching to Conservation)

   • For long-term defense, cells pivot to OXPHOS and mitochondrial efficiency.

   • This requires oxygen, one-carbon metabolism, and cofactors like NAD+, SAM, and spermidine.

3. Failure to Resolve (Exhaustion and Senescence)

   • If the environment (tumor, infection, aging tissue) keeps draining substrates, the system locks into dysfunction.

   • Exhaustion = chronic stimulation with insufficient glucose, methionine, or oxygen.

   • Senescence = oxidative damage, telomere stress, lipid buildup, and failure of mitochondrial quality control.

   • Both are maladaptive outcomes of bioenergetic collapse.

Why this matters beyond T cells

What happens in T cells mirrors what happens across the body in ERM:

• Chronic stress and exposures (toxins, inflammation, poor diet, infections) steadily deplete energy and substrates.

• Systems shift from flexible adaptation → rigid dysfunction.

• The same bioenergetic themes — mitochondrial breakdown, nutrient competition, cofactor shortages — show up in muscle wasting, bone loss, and neurodegeneration.

The opportunity ahead

By recognizing that exhaustion and senescence are not just “failures of will” but failures of energy availability and allocation, we can begin to design smarter interventions. These may include:

• Supporting substrate sufficiency (glucose control, amino acid balance, NAD+ boosters, one-carbon donors like folate/methionine balance).

• Restoring mitochondrial resilience (exercise, spermidine, metabolic modulators).

• Correcting epigenetic drift with targeted nutrients and lifestyle interventions.

The lesson from this review is clear: resilience depends on energy. Just as nations can’t fight wars without supply lines, our immune cells — and our bodies — can’t adapt without a steady, balanced flow of bioenergetic substrates.

🔑 Takeaway: 

CD8+ T cell exhaustion and senescence are not random fates but the predictable result of chronic stress on bioenergetic systems. The ERM framework helps us see them as stages in the broader story of adaptation, depletion, and — if we act early — possible recovery.

Shangguan, Y., Wang, J., Ho, P.-C., & Xu, Y. (2025). CD8+ T cell stressors converge on shared metabolic–epigenetic networks. Trends in Endocrinology & Metabolism. Advance online publication. https://doi.org/10.1016/j.tem.2025.08.009

#T cell exhaustion, #Senescence, #Mitochondrial dysfunction, #Bioenergetic stress, #Exposure-Related Malnutrition (ERM)