Sensory decline in aging and neurodegeneration: A mitochondrial perspective (paper August 2026)

#1

https://www.sciencedirect.com/science/article/pii/S1043661826002379

chatGPT(5.6)paid:

Overall assessment

Adeboye et al., Sensory decline in aging and neurodegeneration: A mitochondrial perspective (2026) is a broad narrative review arguing that mitochondrial dysfunction is a recurring contributor to age-related deterioration of touch, sight, hearing, smell and taste.

Its principal value is organizational: it brings five usually separate sensory literatures into one mitochondrial framework. It does not present new experimental data or establish that mitochondrial dysfunction is the primary cause of sensory ageing. The evidence is strongest for hearing and vision, moderate for smell, and much weaker for taste and touch as sensory modalities.

Summary

The paper proposes the following general sequence:

Ageing, inflammation and environmental injury → mtDNA damage, impaired oxidative phosphorylation, altered mitochondrial dynamics and defective mitophagy → ROS, energy failure, inflammation, senescence and cell death → sensory decline.

Evidence by sensory system

Sense Main evidence reviewed Assessment
Touch UV-induced mitochondrial fragmentation in keratinocytes; TFAM/POLG-mediated mtDNA depletion; SOD2-dependent skin ageing; preservation of worm touch-receptor neurons by BAM15 Mostly evidence about skin ageing, sebaceous glands and wound healing rather than tactile perception. Direct mechanosensory evidence is largely from C. elegans.
Sight mtDNA damage, defective cristae and mitophagy in AMD retinal pigment epithelium; NAD decline, Drp1 activation and RGC death in glaucoma; retinal mitochondrial changes in ageing and ALS models One of the stronger sections because it includes human tissues and patient-derived cells as well as functional animal experiments.
Hearing Drp1-dependent mitophagy; Sirt3–OPA1 regulation; POLG mutations; PARP1/parthanatos; IDH2, Cisd2 and mtDNA variants; interventions including urolithin A, rapamycin, MitoQ and apocynin The strongest mechanistic section, with hearing endpoints such as auditory brainstem responses and compound action potentials. Most intervention evidence remains preclinical.
Smell Complex-I dysfunction and α-synuclein in Parkinson’s models; impaired DNA repair and mitochondrial metabolism in Alzheimer’s models; human olfactory-mucosal transcriptomics and respiration; SOD2-dependent olfactory decline in flies Substantial evidence that mitochondrial abnormalities accompany olfactory pathology, but less evidence that they initiate human hyposmia.
Taste Altered central processing with age; rotenone Parkinson’s models; taste-receptor and mitochondrial transcript changes; Drosophila Alzheimer’s models; long-COVID associations Clearly the weakest section. Much of the evidence is transcriptomic, neurological or associative rather than direct demonstration of mitochondrial causation in taste cells.

Proposed interventions

The paper highlights:

  • Urolithin A to promote mitochondrial and lysosomal quality control.
  • Nicotinamide to restore NAD in glaucoma.
  • Rapamycin to stimulate autophagy/mitophagy.
  • Resveratrol through AMPK–Sirt1–PGC-1α signalling.
  • BAM15 as a mild mitochondrial uncoupler.
  • MitoQ and other antioxidants.
  • Apocynin to inhibit NADPH oxidase.
  • Veliparib to limit PARP1-dependent parthanatos.
  • Kaempferol/Sirt3 activation to improve OPA1 regulation.

These should be regarded as mechanistic leads, not established treatments for human sensory ageing.

What is novel?

The novelty is moderate and mainly conceptual.

  1. All five senses are considered together. Reviews more commonly focus on one organ, such as AMD, glaucoma or age-related hearing loss. Including touch and taste is distinctive.

  2. It identifies recurring mitochondrial modules across sensory organs: mtDNA damage, ROS, ETC dysfunction, altered fission/fusion, mitophagy failure, NAD depletion and impaired ATP generation.

  3. It links ordinary ageing with Alzheimer’s, Parkinson’s, ALS, glaucoma, AMD and long COVID, suggesting that sensory decline may be an accessible early indicator of broader neurodegeneration.

  4. It assembles a cross-sensory pharmacological map. This is useful for generating experiments in which the same mitochondrial intervention could be compared across sensory systems.

What is not novel is the proposition that mitochondrial dysfunction contributes to ageing, neurodegeneration, AMD or hearing loss. The paper supplies no new pathway, dataset, meta-analysis or quantitatively testable unified model. Calling mitochondrial targeting “innovative” therefore overstates the mechanistic originality.

Strengths

  • Broad and reasonably current coverage, with 229 references and several papers from 2024–2026.
  • Useful attention to specific vulnerable cells rather than treating each sensory organ as homogeneous.
  • Inclusion of mtDNA integrity, mitophagy and dynamics—not merely the familiar ROS narrative.
  • Recognition that mitochondrial changes may need to be targeted early.
  • Some effective examples of causality, particularly genetic manipulation of POLG, TFAM, Drp1, Sirt3, OPA1 and Cisd2.
  • The paper occasionally acknowledges biological complexity, such as the age-dependent antagonistic effects of keratinocyte SOD2 deficiency.

Main critique

1. It is not a systematic review

Although the abstract says the literature is discussed “systematically and comprehensively,” there is no search strategy, database list, search date, inclusion criteria, risk-of-bias assessment or evidence-grading framework.

Consequently, the reader cannot determine:

  • whether important negative studies were omitted;
  • how studies were selected;
  • whether evidence quality differed among the five senses;
  • whether publication bias influenced the apparently consistent mitochondrial story.

It should be described explicitly as a narrative or bibliographical review.

2. Association and causation are frequently blurred

Mitochondrial damage is observed in almost every stressed or dying cell. Showing ROS, altered mitochondrial morphology or reduced ATP in diseased tissue does not establish that mitochondrial dysfunction initiated the disease.

The evidence permits three possibilities:

  1. mitochondrial dysfunction causes sensory degeneration;
  2. disease processes cause mitochondrial dysfunction;
  3. both are driven by another process, such as inflammation, protein aggregation, vascular insufficiency or impaired proteostasis.

The paper often moves too quickly from “present in” to “mechanistically responsible for” and then to “pharmacological target.”

3. Normal ageing is conflated with artificial injury and neurodegenerative disease

The review combines physiological ageing with:

  • high-dose hydrogen peroxide;
  • D-galactose treatment;
  • rotenone or MPTP;
  • sodium iodate retinal injury;
  • acoustic trauma;
  • POLG/TFAM depletion;
  • Alzheimer’s and Parkinson’s models;
  • long COVID.

These models are informative but do not necessarily reproduce the slow, multifactorial biology of ordinary human sensory ageing. Pretreatment that protects a young animal against an acute toxin is especially weak evidence for reversing established age-related decline.

4. “Mitochondrial dysfunction” is too broad to be a discriminating mechanism

The term encompasses opposite physiological states. For example:

  • Excessive Drp1-mediated fission is damaging in glaucoma.
  • Reduced Drp1-mediated fission impairs mitophagy and is damaging in cochlear cells.
  • A mitochondrial uncoupler, BAM15, can be protective.
  • Mitochondrial hyperpolarisation is reported in people resistant to glaucomatous injury.
  • SOD2 deficiency can transiently improve wound closure in young mice but becomes harmful with age.

These findings are biologically plausible because mitochondrial responses are tissue-, dose- and time-dependent. But they weaken the idea of one uniformly targetable mitochondrial defect. The review needed a synthesis based on thresholds, timing and cell type rather than a simple “restore mitochondrial homeostasis” conclusion.

5. The evidence is markedly unbalanced

The paper gives all five senses equal conceptual status, but the evidential foundations are not equal:

  • The touch section is dominated by dermatological ageing rather than mechanoreceptor function.
  • The taste row in Table 1 contains only the vague description “metabolic decline.”
  • Hearing and sight receive detailed mechanistic and functional studies.
  • Very little evidence comes from trials in older humans.

The conclusions should have been graded separately for each sense.

6. Therapeutic claims run ahead of clinical evidence

Most reported interventions were tested in cultured cells, worms, flies, zebrafish or rodents. There is little evidence that they preserve or restore sensory function in ageing humans. The review also gives insufficient attention to:

  • achievable human exposure;
  • tissue penetration;
  • duration of treatment;
  • adverse effects;
  • whether treatment was preventive or restorative;
  • off-target mechanisms.

Resveratrol, rapamycin, urolithin A and nicotinamide have multiple biological effects, so protection does not prove that mitochondrial correction was the decisive mechanism.

Specific errors and inconsistencies

Several points should have been corrected before publication:

  • On page 2, the paper says UVB penetrates the skin more deeply than UVA. This is reversed: longer-wavelength UVA generally penetrates more deeply, while UVB is absorbed more superficially. Direct penetration measurements support this distinction.

  • In the urolithin-A passage, “PINK2” should be PARK2, and SQSTM1/p62 is omitted from the listed knockdowns. More importantly, the cited experiment found that p62-dependent lysophagy, rather than mitophagy, was essential for the viability benefit. The original study reports the complete knockdown experiment and conclusion.

  • The same passage alternates between sodium iodate, which was used, and sodium iodide, which was not.

  • Figure 3 says rapamycin “increases mTOR-mediated mitophagy.” Rapamycin inhibits mTOR; the intended statement was presumably that it promotes autophagy/mitophagy through mTOR inhibition.

  • The smell section treats sustained adult olfactory-bulb neurogenesis as generally applicable to humans. It is well established in rodents, but radiocarbon dating found very limited, if any, postnatal neuronal turnover in the adult human olfactory bulb. Bergmann et al.

These are not merely stylistic defects: some alter the mechanistic interpretation.

Relevance to your citrate–acetyl-CoA hypothesis

The paper supports the upstream proposition that deterioration of mtDNA, oxidative phosphorylation, mitochondrial membrane potential, dynamics and quality control can contribute to age-related cellular dysfunction.

It does not, however, test or discuss the proposed downstream pathway:

impaired mitochondrial function → reduced citrate export through SLC25A1 → reduced ACLY-derived nuclear acetyl-CoA → inadequate histone acetylation → impaired transcription or splicing.

There is no substantive discussion of SLC25A1, ACLY, nuclear acetyl-CoA, histone acetylation or splicing. The hearing section’s Sirt3–OPA1 mechanism concerns acetylation of a mitochondrial protein, not histone acetylation. Likewise, reduced citrate synthase in one hearing model concerns mitochondrial TCA function and does not demonstrate reduced citrate export.

Thus, the review is compatible with your hypothesis and supplies relevant sensory phenotypes in which it could be tested, but it provides no direct evidence for the citrate–acetyl-CoA bridge.

Final judgement

This is a useful, timely hypothesis-generating review, especially for identifying vision and hearing as strong experimental systems. Its central conclusion should nevertheless be narrowed to:

Mitochondrial abnormalities are recurrent, sometimes causal and experimentally modifiable components of sensory decline in preclinical models.

It does not yet justify the stronger conclusions that mitochondrial dysfunction is a universal primary driver, that mitochondrial treatments will preserve human sensory function, or that doing so will extend lifespan. I would have recommended major revision to add an explicit review methodology, grade the evidence by sense and species, distinguish cause from consequence, and correct the mechanistic errors above.