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Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability
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DOI：10.1016/j.phrs.2026.108345.png)
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Abstract
En 中文
Frailty is a clinical syndrome of reduced physiological reserve in older adults for which no pharmacological treatment exists and whose cellular basis remains incompletely defined. As life expectancy rises without a comparable extension of healthspan, the absence of a mechanistic account able to guide targeted intervention is a growing clinical problem. The dominant model of primary mitochondrial bioenergetic insufficiency does not accommodate several features of the phenotype. Among the conditions most strongly associated with frailty in aging, obesity, particularly when coupled with sarcopenia, stands out for its rising prevalence and the depth of its systemic metabolic consequences. Drawing on a recent multi-omics characterisation of skeletal muscle in sarcopenic obesity and on the convergent literature in aging metabolism, organelle communication, and redox biology, we propose a complementary framework in which the proximate cellular abnormality of frailty is energetic congestion, a chronic mismatch between substrate input, energetic demand, and the capacity to dispatch the resulting flux through demand-driven oxidative metabolism. In this view the mitochondrion is not failing because fuel is scarce, but because energetic demand declines below the rate at which substrate continues to be delivered, so that substrate persists in relative rather than absolute excess, while mitochondrial adaptability is progressively impaired. The resulting cycle is self-amplifying, anchored in reverse electron transport, and generalises across skeletal muscle, adipose tissue, liver, heart and brain. Strategies that re-engage demand-driven metabolic flux through AMPK activation, substrate restriction, mild mitochondrial uncoupling, modulation of endoplasmic reticulum stress, and clearance of irreversibly congested cells are predicted to produce more durable benefits than energy supplementation, with structured exercise as the prototype of demand-driven recoupling. This perspective offers a path toward a precision pharmacology of frailty grounded in molecular stratification of patients.
Keywords:
ADP
adenosine diphosphate
AMPK
AMP-activated protein kinase
ATP
adenosine triphosphate
BAT
brown adipose tissue
BCAA
branched-chain amino acids
cGAS
cyclic GMP-AMP synthase
ER
endoplasmic reticulum
FDG
fluorodeoxyglucose
FMN
flavin mononucleotide
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide 1
GSH / GSSG
glutathione, reduced and oxidised forms
HFpEF
heart failure with preserved ejection fraction
MAM
mitochondria-associated ER membrane
MASLD
metabolic dysfunction-associated steatotic liver disease
mtDNA
mitochondrial DNA
mTORC1
mechanistic target of rapamycin complex 1
NAD⁺ / NADH
nicotinamide adenine dinucleotide, oxidised and reduced forms
NADPH
nicotinamide adenine dinucleotide phosphate
NLRP3
NLR family pyrin domain containing 3
NMN
nicotinamide mononucleotide
NR
nicotinamide riboside
PGC-1α
peroxisome proliferator-activated receptor γ coactivator 1-alpha
PPAR
peroxisome proliferator-activated receptor
RET
reverse electron transport
ROS
reactive oxygen species
STING
stimulator of interferon genes
TCA
tricarboxylic acid cycle
UCP1
uncoupling protein 1
ULK1
Unc-51-like kinase 1
WASF3
WASP family member 3
Δp
proton-motive force
Δψm
mitochondrial membrane potential
Frailty
Aging
Mitochondrial dysfunction
Sarcopenia
Energetic congestion
Pharmacology of aging
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