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Introduction

Ageing is often discussed as if it were a single, inevitable biological process. Modern geroscience, however, increasingly recognizes that ageing is heterogeneous – comprising both physiological ageing, which is time-dependent and unavoidable, and accelerated ageing, which reflects chronic biological stress and is, at least in part, modifiable.

A recent study from a Japanese research group, published in Signal Transduction and Targeted Therapy, provides a rare level of molecular clarity on this distinction. The work demonstrates that senescent ("ageing") cells do not merely persist passively, but actively survive by exploiting a stressed metabolic and DNA-repair environment. This discovery has important implications for anti-ageing medicine-and for how senescence should be addressed clinically.

1. The Japanese Discovery: A Lactate-Driven Survival Circuit in Senescent Cells

The Japanese investigators identified a previously underappreciated survival dependency in senescent cells. Their key findings can be summarized as follows:

• Senescent cells, despite being growth-arrested, maintain high glycolytic flux;
• This metabolic state generates lactate, which functions as a signaling metabolite rather than metabolic waste;
• Lactate stabilizes an aberrant interaction between PGAM1 (a glycolytic enzyme) and Chk1 (checkpoint kinase 1, a central DNA damage/replication-stress regulator);
• This PGAM1-Chk1 interaction activates downstream survival programs, including HIF-2α and FOXM1, supporting metabolic activity, DNA-damage tolerance, and resistance to apoptosis;
• Pharmacologic disruption of this interaction selectively eliminates senescent cells in experimental models.

In plain terms, the study identifies a terrain-dependent "life-support circuit":

glycolysis → lactate signaling → checkpoint-repair tolerance → senescent persistence

This is a significant advance. It shifts senescence from being viewed as a passive end-stage phenomenon to an active, stress-supported survival state.

2. Why this Matters for Anti-Ageing Medicine

The accumulation of senescent cells with age is strongly associated with tissue dysfunction, chronic inflammation (via SASP), impaired regeneration, and increased disease risk. Accordingly, senolysis-the selective removal of senescent cells-has become a major focus in longevity research.

What distinguishes this Japanese study is that it demonstrates how senescent cells survive. Rather than relying on nonspecific cytotoxicity, the approach exploits a selective vulnerability created by metabolic distortion and DNA-damage tolerance. This provides compelling proof-of-concept that senescent cells can be selectively destroyed.

At the same time, the study aises a deeper and more important question:

Why do senescent cells increasingly depend on glycolysis, lactate, and Chk1-mediated damage tolerance in the first place?

The answer points upstream-to the biological terrain.

3. Senescence, Natural Aging, and Accelerated Ageing

Cellular senescence itself is not inherently pathological. Transient senescence plays essential roles in development, tumour suppression, wound healing, and tissue remodelling. This physiological senescence is normally limited in time and efficiently cleared.

By contrast, accelerated ageing is characterized by the excessive accumulation and persistence of senescent cells. In Integrative Orthomolecular Medicine (IOM), this accelerated senescence is viewed as a downstream manifestation of upstream root drivers-chronic biological stressors that enforce sustained DNA-damage responses, metabolic distortion, and inflammatory feedback loops.

The Japanese PGAM1-Chk1 study addresses precisely this pathological persistence. It does not challenge natural ageing; it explains why senescent cells fail to resolve under chronic stress conditions.

4. Metabolic Terrain: Low-Carbohydrate and Ketogenic Strategies

A central implication of the Japanese discovery is that senescent cells are metabolically supported. Their persistence depends on glycolysis and lactate signaling.

Independent work in Nature Metabolism has shown that senescent cells can adopt PDK4-dependent aerobic glycolysis with increased lactate production, even while remaining growth-arrested. This mirrors the metabolic dependency exploited by the PGAM1-Chk1 interaction.

From this perspective, low-carbohydrate and ketogenic dietary strategies occupy a legitimate place in anti-ageing medicine-not as senolytic therapies, but as terrain-modifying interventions:

• Reduced glucose availability lowers glycolytic flux;
• Reduced glycolysis lowers lactate generation and signaling;
• Reduced lactate signaling destabilizes senescent persistence.

Such approaches are best understood as senomorphic-altering the environment that supports senescent survival-rather than as agents that directly kill senescent cells.

5. Oxidative Stress, Inflammation, and Chk1 Dependence

Chk1 is not an "ageing protein"; it is a stress-response kinase. Persistent reliance on Chk1 reflects ongoing DNA damage and replication stress, often driven by oxidative and inflammatory burden.

A broad literature demonstrates that:

• Chronic oxidative stress promotes DNA-damage response signaling and senescence;
• Inflammatory signaling reinforces senescence through SASP feedback loops;
• Reduction of oxidative and inflammatory load can attenuate stress-induced senescence in multiple models.

The Japanese study's emphasis on Chk1-mediated damage tolerance therefore implicitly implicates redox imbalance and chronic inflammation as upstream drivers of senescent persistence.

Orthomolecular medicine addresses this domain directly by restoring antioxidant capacity, redox balance (氧化还原系统), mitochondrial function, and micronutrient sufficiency-not by inhibiting Chk1, but by reducing the biological need for checkpoint-dependent survival.

6. Endocrine Context, the ICV axis, and BHRT

Although the Japanese study does not explicitly examine hormonal regulation, its findings intersect with endocrine biology in important ways.

Within IOM, the Insulin-Cortisol-Vitamin C (ICV) axis integrates metabolic control, stress physiology, and redox regulation:

• Insulin resistance and cortisol dysregulation increase oxidative stress, mitochondrial dysfunction, and DNA-damage burden;
• Vitamin C plays essential roles in antioxidant defence, adrenal steroidogenesis, and mitochondrial redox regulation;

These factors directly influence the same stressors-glycolytic reprogramming and checkpoint dependence-identified in the Japanese work.

Similarly, bioidentical hormone replacement therapy (BHRT) influences mitochondrial function, oxidative stress signaling, and DNA-damage response pathways. Emerging human data suggest that hormonal milieu can alter circulating senescence-associated biomarkers, indicating that endocrine context modulates senescence biology, even if precise molecular links remain under investigation.

Importantly, neither the ICV axis nor BHRT should be viewed as direct anti-senescence treatments. Rather, they may reduce the upstream drivers that force cells into stress-stabilized senescence.

7. The Two-Tier Anti-Ageing System

The Japanese PGAM1-Chk1 discovery fits naturally within a Two-Tier model of anti-ageing medicine:

• Tier 1: Restorative Medicine
  Reduce upstream drivers-metabolic distortion, oxidative stress, inflammation, endocrine imbalance-that accelerate senescent formation and persistence.
• Tier 2: Targeted / Regenerative Interventions
  Apply senolytics or other targeted tools after the biological terrain has been stabilized.

The Japanese study represents a powerful Tier-2-relevant tool, but its own mechanistic logic reinforces why Tier-1 terrain correction is indispensable for durable benefit.

Conclusion

The Japanese discovery that senescent cells depend on glycolysis-derived lactate signaling and Chk1-mediated DNA-damage tolerance provides a strong mechanistic foundation for a terrain-based understanding of accelerated ageing.

It confirms that senescent cells are active survivors, maintained by distorted metabolism and stress signaling. Removing such cells is important. Preventing their accelerated formation and persistence is more important.

This balance-between selective removal and upstream prevention-is the essence of Integrative Orthomolecular Medicine and of rational anti-ageing medicine in the 21st century.

Disclaimer

This article is for scientific discussion and information exchange only and does not constitute medical advice. Any intervention discussed should be undertaken under the supervision of a trained and experienced healthcare professional.

Key References and Further Reading – Primary Mechanistic Anchor (Japanese Discovery)

1. Mikawa T, et al. Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions. Signal Transduction and Targeted Therapy. 2025 Dec 15;10(1):402. doi: 10.1038/s41392-025-02502-6 PMID: 41392167; PMCID: PMC12702999.

Metabolic Reprogramming, Glycolysis, and Lactate in Senescence

2. Dou X, et al. PDK4-dependent hypercatabolisms and lactate production of senescent cells promotes cancer malignancy. Nature Metabolism. 2023 Nov;5(11):1887-1910. doi: 10.1038/s42255-023-00912-w. PMID: 37903887; PMCID: PMC10663165 . (Errata: Nat Metab. 2024 May;6(5):980; Jul;6(7):1416.)
3. Sabbatinelli J, et al. Where metabolism meets senescence: focus on endothelial cells.
   Frontiers in Physiology. 2019;10:1523. doi: doi:10.3389/fphys.2019.01523. PMID: 31920721; PMCID: PMC6930181 .
4. Liu B, et al. Lipid and glucose metabolism in senescence. Frontiers in Nutrition. 2023;10:1157352. doi: doi:10.3389/fnut.2023.1157352. PMID: 37680899; PMCID: PMC10481967 .

Oxidative Stress, DNA Damage Response, and Senescence

5. Stojanovic B, et al. Oxidative stress-driven cellular senescence: mechanistic crosstalk and therapeutic horizons. Antioxidants (Basel). 2025 Aug 12;14(8):987. doi: doi:10.3390/antiox14080987. PMID: 40867884; PMCID: PMC12383077 .
6. Wang L, et al. Exploiting senescence for the treatment of cancer. Nature Reviews Cancer. 2022 Jun;22(6):340-355. doi: doi:10.1038/s41568-022-00450-9. PMID: 35241831.

Physiological vs. Pathological Senescence

7. Huang W, et al. Cellular senescence: the good, the bad and the unknown. Nature Reviews Nephrology. 2022 Oct;18(10):611-627. doi: 10.1038/s41581-022-00601-z PMID: 35922662; PMCID: PMC9362342.

Metabolic Interventions and Ageing Context

8. Wei S-J, et al. Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Science Advances. 2024 May 17;10(20):eado1463. doi: 10.1126/sciadv.ado1463 PMID: 38758782; PMCID: PMC11100565

Inflammation, SASP, and Senescent Persistence

10. Coppé J-P, et al. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology. 2010;5:99-118. doi: 10.1146/annurev-pathol-121808-102144 PMID: 20078217; PMCID: PMC4166495 .

Lifestyle Modulation and Senescent Burden

11. Englund DA, et al. Exercise reduces circulating biomarkers of cellular senescence in humans. Aging Cell. 2021 Jul;20(7):e13415. doi: 10.1111/acel.13415. PMID: 34101960; PMCID: PMC8282238 .

Systems-Level Aging Framework

12. Cheng RZ. A Two-Tier Systems Medicine Model for Human Longevity: Restorative and Regenerative Pathways to the 120-Year Lifespan Potential. Preprints.org. 2025; 2025121191. doi: doi.org/10.20944/preprints202512.1191.v1

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Editorial Review Board:

Jennifer L. Aliano, M.S., L.Ac., C.C.N. (USA)
Albert G. B. Amoa, MB.Ch.B, Ph.D. (Ghana)
Seth Ayettey, M.B., Ch.B., Ph.D. (Ghana)
Ilyès Baghli, M.D. (Algeria)
Greg Beattie, Author (Australia)
Barry Breger, M.D. (Canada)
Ian Brighthope, MBBS, FACNEM (Australia)
Gilbert Henri Crussol, D.M.D. (Spain)
Carolyn Dean, M.D., N.D. (USA)
Ian Dettman, Ph.D. (Australia)
Susan R. Downs, M.D., M.P.H. (USA)
Ron Ehrlich, B.D.S. (Australia)
Hugo Galindo, M.D. (Colombia)
Gary S. Goldman, Ph.D. (USA)
William B. Grant, Ph.D. (USA)
Claus Hancke, MD, FACAM (Denmark)
Patrick Holford, BSc (United Kingdom)
Ron Hunninghake, M.D. (USA)
Bo H. Jonsson, M.D., Ph.D. (Sweden)
Dwight Kalita, Ph.D. (USA)
Felix I. D. Konotey-Ahulu, M.D., FRCP (Ghana)
Peter H. Lauda, M.D. (Austria)
Fabrice Leu, N.D., (Switzerland)
Alan Lien, Ph.D. (Taiwan)
Homer Lim, M.D. (Philippines)
Stuart Lindsey, Pharm.D. (USA)
Pedro Gonzalez Lombana, M.D., Ph.D. (Colombia)
Diana MacKay (Gifford-Jones), M.P.P. (Canada)
Victor A. Marcial-Vega, M.D. (Puerto Rico)
Juan Manuel Martinez, M.D. (Colombia)
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Dr.Aarti Midha M.D., ABAARM (India)
Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico)
Karin Munsterhjelm-Ahumada, M.D. (Finland)
Sarah Myhill, MB, BS (United Kingdom)
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Zhiyong Peng, M.D. (China)
Pawel Pludowski, M.D. (Poland)
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Selvam Rengasamy, MBBS, FRCOG (Malaysia)
Jeffrey A. Ruterbusch, D.O. (USA)
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Jagan Nathan Vamanan, M.D. (India)
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Andrew W. Saul, Ph.D. (USA), Founding & Former Editor
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