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Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening
Roland Patai, Krish Patel, Boglárka Csík, Rafał Gulej, Raghavendra Yelahanka Nagaraja, Dorina Nagy, Siva Sai Chandragiri, Santny Shanmugarama et al.. GeroScience, 2025-04-02
Topic: Brain proteins, microglia and lab models
Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) contribute to vascular cognitive impairment and dementia (VCID), with aging and hypertension being key risk factors. Mitochondrial oxidative stress is a hallmark of cerebrovascular aging, leading to endothelial dysfunction. This study tests the hypothesis that increased mitochondrial oxidative stress contributes to age-related CMH susceptibility and evaluates the mitochondrial-targeted antioxidative peptide SS-31 (elamipretide) as a potential protective agent in an aged, hypertensive mouse model. Concurrently, we developed a high-throughput, machine learning-driven imaging pipeline to enhance CMH quantification and facilitate the screening of anti-aging vasoprotective interventions. To detect CMHs, brain sections were labeled with diaminobenzidine (DAB) and digitized using a slide scanner-based imaging platform. We developed multiple quantification tools, including color space transformation for enhanced contrast separation and a supervised machine-learning approach utilizing a random forest algorithm to generate whole-brain 3D reconstructions and precisely localize CMHs. We optimized a semi-automated detection method integrating color space transformation and machine learning, benchmarking it against traditional manual counting and color deconvolution-based approaches. While SS-31 treatment did not significantly mitigate hypertension-induced CMH burden in aged mice, our high-throughput imaging pipeline provided a reliable, scalable, and unbiased approach to CMH detection, reducing processing time while improving accuracy. This methodological advancement paves the way for future preclinical studies evaluating therapeutic strategies for cerebrovascular protection in aging. Our findings underscore the need for multi-targeted interventions to mitigate CMH-related neurovascular impairments and prevent VCID.
Key findings
- While SS-31 treatment did not significantly mitigate hypertension-induced CMH burden in aged mice, our high-throughput imaging pipeline provided a reliable, scalable, and unbiased approach to CMH detection, reducing processing time while improving accuracy.
- Our findings underscore the need for multi-targeted interventions to mitigate CMH-related neurovascular impairments and prevent VCID.
Why it matters
In an aged hypertensive mouse model, the drug SS-31 did not significantly reduce cerebral microhemorrhage burden, though a new imaging pipeline was developed. This is preclinical animal work and does not establish any treatment, cure or prevention for dementia in humans.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (GeroScience) |
| Journal's citation record | 1 / 4 | GeroScience: journal h-index 83 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 15 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 8.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 15 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Ádám Nyúl‐Tóth: h-index 37 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | University of Oklahoma Health Sciences Center: institution h-index 557 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40169521) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
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Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Patai, R., Patel, K., Csík, B., Gulej, R., Nagaraja, R. Y., Nagy, D., et al. (2025). Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening. GeroScience. https://doi.org/10.1007/s11357-025-01634-5
Vancouver
Patai R, Patel K, Csík B, Gulej R, Nagaraja RY, Nagy D, et al. Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening. GeroScience. 2025. doi:10.1007/s11357-025-01634-5. PMID: 40169521.
BibTeX
@article{patai2025-40169521,
author = {Patai, Roland and Patel, Krish and Csík, Boglárka and Gulej, Rafał and Nagaraja, Raghavendra Yelahanka and Nagy, Dorina and Chandragiri, Siva Sai and Shanmugarama, Santny and others},
title = {{Aging, mitochondrial dysfunction, and cerebral microhemorrhages: a preclinical evaluation of SS-31 (elamipretide) and development of a high-throughput machine learning-driven imaging pipeline for cerebromicrovascular protection therapeutic screening}},
journal = {GeroScience},
year = {2025},
doi = {10.1007/s11357-025-01634-5},
pmid = {40169521},
url = {https://doi.org/10.1007/s11357-025-01634-5}
}
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