Role of Succinate Dehydrogenase in Age-Related Th17 Inflammation.

Mitochondrial complex II (SDH) expression was upregulated in CD4+ T cells from older adults compared to younger adults.

• Younger adults averaged 31.58 years with BMI 21.14 kg/m2; older adults averaged 64.81 years with BMI 21.95 kg/m2.
• Participants were lean and normoglycemic, controlling for metabolic confounders.
• CD4+ T cells were isolated for comparison between the two age groups (younger: 25-40 years old; older: 60-80 years old).

T cells from older adults produced higher amounts of Th17 cytokines IL-17A/F and IL-21, and the Th17-supportive cytokine IL-6, compared to T cells from younger adults.

• Cytokines measured included IL-17A/F, IL-21, and IL-6.
• These cytokines are generally considered proinflammatory.
• This was established in prior work referenced by the authors and confirmed in the current study.

SDH activation in T cells from older adults induced heightened oxidation of succinate and disrupted the fumarate-to-succinate ratio.

• Succinate oxidation was elevated in T cells from older adults compared to younger adults.
• The fumarate-to-succinate ratio was disrupted as a consequence of hyperactivated SDH.
• Both pharmacological and genetic modulation of SDH were used to evaluate these metabolic changes.
• Mitochondrial structure, function, and metabolites were quantified as outcome measures.

SDH hyperactivation in T cells from older adults stabilized HIF-1α and promoted Th17 cytokine production.

• HIF-1α stabilization was identified as a mechanistic link between SDH activity and Th17 inflammation.
• Disruption of the fumarate-to-succinate ratio is implicated in HIF-1α stabilization.
• Th17 cytokine production was elevated in association with SDH hyperactivation and HIF-1α stabilization.

Genetic and pharmacological inhibition of SDH in T cells from older adults lowered proinflammatory cytokine production.

• Both genetic (knockdown/knockout) and pharmacological approaches were used to inhibit SDH.
• Inhibition of SDH reduced Th17-associated proinflammatory cytokines in T cells from older adults.
• This finding supports a causal role for SDH in driving age-related Th17 inflammation.

Exogenous addition of cell-permeable succinate to T cells from younger adults induced SDH protein expression and recapitulated the proinflammatory Th17 profile observed in T cells from older adults.

• Cell-permeable succinate was added exogenously to T cells from younger adults (avg: 31.58 years).
• This treatment increased SDH protein levels in T cells from younger adults.
• The resulting cytokine profile mirrored the proinflammatory Th17 profile characteristic of T cells from older adults.
• This experiment provided evidence that elevated succinate availability is sufficient to drive the age-associated inflammatory phenotype.