https://www.sciencedirect.com/science/article/pii/S1043661826002604?via%3Dihub
chatGPT(5.5paid):
Obviously I disagree with a lot of this paper although I think mitochondria are at the core of frailty.
This is an Opinion/Perspective article, rather than a new experimental study. Its main contribution is a proposed mechanistic framework for frailty called “energetic congestion”, which reframes mitochondrial dysfunction in ageing as a failure to match substrate supply to declining energetic demand rather than simply a failure to make enough ATP.
Summary
The conventional interpretation of frailty is that ageing mitochondria lose respiratory capacity, causing an energetic deficit. The authors accept that mitochondrial dysfunction occurs, but argue that this explanation is incomplete. They point to an apparent paradox: if ageing cells were genuinely energy-starved, AMPK—the canonical sensor of low cellular energy—should be activated, yet AMPK activity is often reduced in aged muscle, adipose tissue and liver. At the same time, cellular ATP demand declines because of reduced physical activity, sarcopenia, anabolic resistance and loss of brown-adipose thermogenesis.
Their alternative is:
maintained substrate supply + falling ATP demand + impaired metabolic adaptability → energetic congestion.
In their model, fatty acids and glucose continue entering cells while ATP consumption decreases. Consequently:
substrate delivery exceeds demand-driven oxidative disposal.
The resulting mitochondrial state has low ADP availability, high proton-motive force, a highly reduced ubiquinone pool and increased NADH/NAD⁺. This favours reverse electron transport (RET) through Complex I, generating ROS and initiating a self-reinforcing deterioration in mitochondrial function.
The paper breaks the proposed congested state into six linked mechanisms:
-
PPAR activation becomes uncoupled from AMPK.
Fatty acids continue activating PPARα/δ and fatty-acid oxidation genes even though energetic demand is low. AMPK, meanwhile, is suppressed. -
Oxidative throughput becomes bottlenecked.
Fatty-acid uptake/β-oxidation continues but complete oxidation cannot keep pace, producing long-chain acylcarnitine accumulation and loss of free carnitine. -
Reductive stress develops.
Reduced ADP demand slows electron transport, NADH accumulates and the NADH/NAD⁺ ratio rises. TCA-cycle enzymes are inhibited and RET becomes favourable. -
Redox defence fails on both sides.
RET increases ROS generation while suppression of the pentose-phosphate pathway reduces NADPH production and therefore glutathione recycling. -
Autophagy/mitophagy become impaired.
Low AMPK reduces ULK1 activation and associated autophagic responses, preventing damaged mitochondria from being efficiently removed. ER stress and WASF3-mediated respiratory supercomplex disruption may add to this failure. -
Protein is mobilised for anaplerosis.
Increased BCAA catabolism helps maintain restricted TCA-cycle flux but potentially consumes muscle protein, further worsening sarcopenia.
The diagram on page 2 is essentially the paper’s whole hypothesis in visual form: decreased ATP demand raises Δp, promotes RET/ROS and creates feedback between reductive stress, incomplete β-oxidation, redox failure, impaired mitophagy and muscle-protein mobilisation.
Extension beyond muscle
Although inspired partly by the authors’ previous multi-omics work in sarcopenic-obese mice, they argue that the same architecture could apply across tissues.
In skeletal muscle, reduced contraction directly lowers ATP turnover. In adipose tissue, loss of brown-fat uncoupling removes a systemic substrate-disposal mechanism while dysfunctional white fat releases fatty acids. In liver, the authors regard MASLD as something resembling a well-characterised example of energetic congestion. In the heart, they suggest HFpEF may represent a related state in which substrate disposal becomes mismatched to workload. In the brain, they speculate that reduced synaptic demand and impaired glucose utilisation could create an analogous state.
They also connect mitochondrial dysfunction to systemic frailty through ER–mitochondrial contact defects, mtDNA release, cGAS–STING, NLRP3 activation and inflammaging.
Therapeutic implications
A major consequence of the model is that therapy should not primarily attempt to “give mitochondria more energy.” Instead, treatment should restore metabolic throughput and demand–supply coupling.
The authors therefore favour interventions such as exercise, AMPK activation, caloric restriction/intermittent fasting, GLP-1/GIP-mediated substrate restriction, mild mitochondrial uncoupling and possibly interventions against ER stress. NAD⁺ precursors are repositioned as interventions against reductive stress rather than as generic mitochondrial “fuel.” Senolytics are proposed for cells whose congested state has become irreversible.
Exercise is presented as the ideal intervention because it directly raises ADP/ATP turnover, lowers Δp, increases forward respiratory-chain flux, activates AMPK and PGC-1α and should therefore suppress RET.
What is novel?
The authors themselves explicitly acknowledge that none of the individual biochemical mechanisms is new. Their novelty lies in joining them into a different causal architecture.
1. Reversing the direction of mitochondrial causality
The most interesting conceptual move is:
conventional view
mitochondrial failure → insufficient ATP → frailty
versus their proposed sequence:
declining energetic demand → mitochondrial congestion → RET/redox damage → declining mitochondrial capacity → frailty.
That is a significant distinction. Mitochondrial dysfunction becomes partly a consequence of chronically reduced metabolic throughput rather than simply the initiating lesion.
2. Treating high Δp as potentially pathological in ageing
The model focuses attention on a mitochondrion that is relatively over-reduced and highly polarised at rest, rather than chronically incapable of generating membrane potential.
That produces a particularly clear experimentally testable prediction:
frail/congested cells should show elevated resting Δψm, elevated NADH/NAD⁺ and evidence of RET.
The authors identify those measurements as among the most discriminating tests between their model and a simple energetic-deficiency model.
3. Connecting inactivity to RET
The proposed chain
low ATP turnover → low ADP → high Δp → reduced Q pool → RET → ROS
is probably the paper’s most distinctive mechanistic synthesis.
It offers an unusually direct biochemical explanation for why inactivity might damage mitochondrial function rather than merely result from it.
4. Frailty as loss of mitochondrial adaptability
The paper also offers an attractive correspondence between the clinical definition and cellular mechanism:
clinical frailty = inability to increase physiological output when challenged
and
mitochondrial congestion = a system already metabolically constrained and unable to increase throughput when challenged.
That conceptual correspondence is elegant and potentially useful.
5. A pharmacological prediction
The framework predicts that interventions increasing throughput/demand or controlled dissipation should outperform interventions that simply increase energetic substrate or cofactor availability.
This makes the hypothesis falsifiable rather than merely descriptive.
Critique
I think the framework is interesting, but several steps in the causal chain are much less secure than the paper sometimes implies.
1. The central assumption—high ATP/low ADP in frail tissue—is not actually demonstrated
This is the most important weakness.
Much of the mechanism depends on:
reduced ATP demand → low ADP → high Δp → reduced Q → RET.
But the paper does not show that frail human skeletal muscle actually has:
- unusually high ATP/ADP,
- elevated resting Δψm,
- a strongly reduced ubiquinone pool,
- elevated mitochondrial NADH/NAD⁺,
- or substantial chronic RET.
Indeed, the authors correctly list these as experiments still needing to be done.
So the paper currently has strong evidence for many components, but weaker evidence that those components are arranged in the causal order proposed.
That distinction is crucial.
2. Reduced AMPK does not necessarily prove energy surplus
The authors use low AMPK activity as an argument against energetic deficiency:
a cell in genuine energetic deficit should engage AMPK.
That is directionally reasonable but too strong.
AMPK signalling can itself become defective with ageing because of altered upstream kinases, phosphatases, localisation, glycogen sensing, inflammation or altered AMPK-subunit expression.
Consequently:
low AMPK ≠ necessarily high cellular energy charge.
The paper sometimes treats dysfunctional energy sensing and high energy charge as if they were interchangeable explanations.
They are not.
3. Capacity and demand are difficult to disentangle
A frail person’s ATP turnover may indeed be low because they perform less work.
But their low activity may itself result from reduced mitochondrial capacity.
This creates a causality problem:
mitochondrial dysfunction → reduced physical activity → reduced demand
versus
reduced physical activity → congestion → mitochondrial dysfunction.
Both almost certainly occur, forming a feedback loop.
The paper would be stronger if it presented energetic congestion primarily as a positive-feedback mechanism amplifying frailty, rather than suggesting it is generally the initiating event.
4. RET may be overemphasised
RET is biochemically plausible under high Δp and a highly reduced Q pool and is very important in some settings such as reperfusion.
But demonstrating that chronic RET is quantitatively important in ordinary ageing mammalian tissues is considerably harder.
The paper relies heavily on RET to make the whole system self-amplifying.
Thus the most decisive experiment would probably be:
demonstrate increased RET-derived ROS directly in aged/frail mammalian muscle at rest and show that selectively suppressing RET improves the phenotype.
Until that is demonstrated, RET is a plausible centrepiece rather than an established one.
5. Sarcopenic obesity may be a biased starting point
The model originates substantially from a multi-omics study of sarcopenic obesity, which is almost the ideal condition in which to find simultaneous excess substrate delivery and reduced muscular demand.
Generalising from this to frailty in a lean older person is considerably harder.
The authors try to solve this by arguing that ectopic lipid and adipose redistribution can maintain local fatty-acid supply even without obesity. That is plausible, but it needs direct demonstration.
The model may therefore fit:
sarcopenic obesity > metabolic frailty > general frailty
in descending strength.
6. Some organ-system extensions are substantially more speculative
The muscle argument is relatively coherent.
The liver analogy is also plausible.
The brain is much weaker. The authors themselves use language such as “tempting to speculate.” Reduced FDG uptake does not straightforwardly establish substrate oversupply relative to demand, and neurons have very different metabolic constraints from sedentary skeletal muscle.
Likewise, the heart is unusual because ATP demand remains extremely high and cannot simply decline with inactivity.
So “energetic congestion” may describe several different metabolic states that share endpoints without necessarily sharing one upstream mechanism.
7. Exercise does not uniquely support the hypothesis
Exercise is extremely effective against frailty, and the authors interpret this as evidence for increasing energetic demand.
But exercise simultaneously causes:
- mitochondrial biogenesis,
- increased mitophagy,
- vascular adaptation,
- improved insulin sensitivity,
- muscle hypertrophy,
- altered myokines,
- inflammatory changes,
- satellite-cell effects,
- improved neuromuscular function.
Therefore exercise cannot by itself discriminate between energetic congestion and conventional mitochondrial-deficiency models.
A cleaner experiment would increase ATP turnover without generating the whole exercise-adaptation programme.
8. The uncoupling prediction is interesting but risky
The proposal that mild uncoupling might improve frailty follows logically from the model:
↓Δp → ↓RET → increased electron flow.
But in a person whose mitochondrial reserve is genuinely low, uncoupling could make ATP production less efficient and potentially worsen weakness.
This actually creates an excellent test of the framework because it predicts different responses in two patient groups:
- congested/high-Δψm phenotype → uncoupling might help
- low-capacity/low-Δψm phenotype → uncoupling might harm
The paper’s emphasis on molecular stratification is therefore particularly important.
What would most convincingly test the paper?
The paper becomes substantially more compelling if one experiment produces the following phenotype in frail human muscle:
resting frail muscle
↑ Δψm
↑ NADH/NAD⁺
↑ QH₂/Q
↓ ADP/ATP
↑ long-chain acylcarnitines
↑ RET-specific ROS
followed by exercise or another demand-raising intervention producing:
↓ Δψm
↓ NADH/NAD⁺
↓ QH₂/Q
↓ RET
↓ acylcarnitines
↑ oxidative flux.
That would directly demonstrate the proposed causal state rather than infer it from separate literatures.
Conversely, finding low resting Δψm and an oxidised NAD pool in frail muscle would seriously challenge the central model.
Overall assessment
I would regard this as a conceptually strong and genuinely interesting hypothesis paper, rather than evidence that energetic congestion has already been demonstrated as the mechanism of frailty.
Its strongest contribution is not any individual pathway but the proposed causal chain:
falling demand → elevated Δp/reductive pressure → RET → mitochondrial damage → impaired mitophagy → declining capacity → still lower demand.
That feedback loop provides a potentially useful bridge between physical inactivity, mitochondrial dysfunction and progressive frailty.
Its main vulnerability is also very clear: the crucial energetic state at the centre of the model—high resting Δψm, reductive stress and RET in frail human tissues—has largely been inferred rather than measured. The authors recognise this, which makes their proposed measurements of Δψm, NADH/NAD⁺ and RET particularly important.