How growth hormone excess accelerates liver aging via glycation stress

#1

“Glycation-lowering strategies may serve as effective treatments for alleviating GH-induced metabolic and inflammatory disruptions in the liver, offering a promising avenue for addressing age-related metabolic diseases associated with GH dysregulation.”

BUFFALO, NY — November 18, 2025 — A new research paper was published in Volume 17, Issue 10 of Aging-US on October 3, 2025, titled “Growth hormone excess drives liver aging via increased glycation stress.”

In this study, led by first author Parminder Singh alongside with corresponding authors Pankaj Kapahi from the Buck Institute for Research on Aging and Andrzej Bartke from Southern Illinois University School of Medicine, researchers investigated how elevated growth hormone (GH) levels contribute to liver aging and dysfunction. They found that excess GH disrupts liver metabolism in ways that resemble aging-related liver damage. The study suggests that managing glycation stress may help prevent or treat liver diseases linked to abnormal hormone levels.

Excess GH is known to cause different disorders, but its long-term impact on internal organs like the liver has remained unclear. To address this, researchers used a mouse model engineered to overproduce bovine GH and examined how chronic hormone exposure affects liver function over time.

“Pathological conditions such as acromegaly or pituitary tumors result in elevated circulating GH levels, which have been implicated in a spectrum of metabolic disorders, potentially by regulating liver metabolism.”

The team found that young mice with GH overexpression showed molecular and cellular patterns similar to those in naturally aged livers. In both groups, genes involved in metabolism were suppressed, while those linked to immune and inflammatory responses were activated. On one hand, the metabolic changes were associated with the buildup of advanced glycation end products, harmful compounds formed when sugars attach to proteins or fats without proper regulation. On the other hand, the immune and inflammatory changes reflected a process known as “inflammaging,” a form of chronic, low-grade inflammation commonly associated with aging. By revealing the overlap between hormone-driven and age-related liver dysfunction, the study provides new insight into how GH may accelerate aging processes.

https://www.eurekalert.org/news-releases/1106418

Research paper (open access)

Growth hormone excess drives liver aging via increased glycation stress

#2

ChatGPT5.1 Summary

Here is a systematic summary, novelty-identification and critique of the paper titled “Growth hormone excess drives liver aging via increased glycation stress” by Singh et al., published in Aging (Albany NY) (2025) (Aging-US)

Executive Summary

  • The authors examine how chronic elevated levels of growth hormone (GH) affect liver ageing and metabolism, using a transgenic mouse model (bovine GH-overexpressing, “bGH-Tg”). (Aging-US)
  • They perform bulk RNA-seq of livers from ~10-month old bGH-Tg vs wild-type (WT) mice, showing substantial transcriptomic dysregulation: over 4,000 genes differentially expressed (≈3,169 up, ≈1,193 down) in bGH-Tg vs WT. (Aging-US)
  • Pathway analyses show upregulation of inflammatory/immune responses and downregulation of metabolic/detoxification pathways (fatty acid metabolism, bile secretion, oxidative phosphorylation) in bGH-Tg livers. (Aging-US)
  • Comparing the bGH-Tg liver transcriptome with aged WT mouse liver (24-mo vs 10-mo) they find ~596 overlapping differentially­expressed genes (DEGs) and a positive correlation (r≈0.30) suggesting GH excess drives a transcriptional programme reminiscent of liver ageing. (Aging-US)
  • They measure accumulation of advanced glycation end-products (AGEs) in bGH-Tg liver and serum; show elevated CML and MGH-1 (but not CEL) in GH-excess mice. (Aging-US)
  • They test an intervention: a “Gly-Low” dietary cocktail (alpha-lipoic acid, nicotinamide, thiamine HCl, piperine, pyridoxamine) aimed at reducing glycation stress, and report improvements in metabolic parameters (body weight gain, fat mass, fasting glucose, glucose tolerance, insulin sensitivity), and improved functional/motor outcomes (grip strength, rotarod). (Aging-US)
  • RNA-seq on Gly-Low treated bGH-Tg livers reveals ~163 overlapping DEGs (with negative correlation r≈–0.50) relative to the bGH-Tg vs WT comparison, suggesting partial reversal of GH-induced transcriptional changes. (Aging-US)
  • They also perform metabolomic (reduced GSH/GSSG ratio, NADPH levels) and protein validation (e.g., reduced SREBF1, CLOCK, PPAR-α in bGH-Tg; rescue of PPAR-α by Gly-Low) to support mechanistic inferences. (Aging-US)
  • Conclusion: chronic GH excess can accelerate hepatic ageing through glycation/AGE accumulation, inflammatory activation, metabolic down-regulation; glycation-lowering interventions may mitigate these effects. (Aging-US)

Novelty / Contribution

What this paper adds:

  1. Linking GH excess to hepatic ageing signatures: Prior work has shown GH connection to metabolism, lifespan (e.g., GH-deficient mice live longer) but this paper provides a relatively comprehensive transcriptomic comparison of GH-overexpressing livers with naturally aged livers to demonstrate overlap. That gives stronger support to the idea that GH over-exposure accelerates ageing at the molecular level in the liver.
  2. AGE accumulation as mechanistic mediator: While AGEs (advanced glycation end-products) have been implicated in ageing and metabolic disease, the specific demonstration that GH-excess leads to elevated AGEs in liver/serum and that lowering glycation stress via the Gly-Low cocktail ameliorates many of the GH-driven pathologies is new (or at least under-explored) in the GH/aging context.
  3. Intervention via glycation-lowering diet in GH-excess model: The use of the dietary supplementation (alpha-lipoic acid, nicotinamide, etc.) to reverse aspects of the GH‐driven transcriptome/metabolic defects is a translational tag—especially for a longevity/healthspan-oriented audience.
  4. Combined multi-omics (transcriptome, metabolome, proteome) in a GH-overexpression model: The integrated approach adds mechanistic depth (e.g., showing oxidative stress markers, transcription factor changes, detoxification enzyme expression changes) beyond a purely descriptive study.
  5. For the longevity/healthspan community (your domain): This provides another axis (GH excess → glycation → aging) that may be modifiable; and suggests glycation interventions may have value in conditions of endocrine dysregulation (e.g., acromegaly) and potentially broader metabolic/liver ageing contexts.

Critique: Strengths & Weaknesses

Strengths

  • The model is well‐chosen (bGH-Tg mice) for GH excess.
  • Large gene expression data (≈4 k DEGs) with pathway/TF analysis offers mechanistic insight.
  • Comparative approach to naturally aged liver strengthens argument for accelerated ageing.
  • Use of intervention (Gly-Low) to show reversibility adds translational significance.
  • Use of multi‐technique validation (metabolomics, protein blots) is good.
  • Open access, transparent methods, and relatively large sample size (~150 mice total) provide robustness.

Weaknesses / Caveats

  1. Model relevance to humans: The bGH-Tg model uses bovine GH overexpression in mice—differences in species, GH/IGF-1 axis, and the fact that humans with GH excess (e.g., acromegaly) are a fairly rare pathological condition mean that generalising to “normal ageing” or human liver ageing should be cautious. Moreover, GH levels in transgenic models may be far supra-physiological.
  2. Causality vs correlation: While the overlap between GH-excess and aging transcriptomes is shown, the correlation (r≈0.30) is moderate; so GH excess only accounts for part of the ageing signature. The study shows associations (AGE accumulation, transcriptome shift, metabolic decline) but does not definitively prove that AGEs are the causal mediators of the GH-driven ageing phenotype. The Gly-Low intervention supports the idea, but still leaves room for off-target effects (e.g., nicotinamide may affect many pathways).
  3. Intervention specificity and translational dosing: The dietary Gly-Low cocktail uses relatively high doses (e.g., nicotinamide ~8.57 g/kg in diet, etc) in mice; translating this to humans, and dissecting which component(s) are effective vs synergistic vs redundant is not clear. Also the nomenclature “Gly-Low” suggests glycation lowering, but multiple compounds used may act via other mechanisms (antioxidant, NAD metabolism, etc). So attributing effect solely to “glycation reduction” is a little simplistic.
  4. Focus on liver only: The study emphasizes the liver, which is appropriate for GH’s metabolic target. But ageing is systemic; it would strengthen the argument if non‐hepatic tissues (kidney, brain, muscle) were also profiled for similar GH/AGE impacts. The authors note this limitation. (Aging-US)
  5. Duration/age of mice: They used 10-month old transgenic mice vs 24-month old WT for ageing comparison. Mouse lifespan (~2-3 years) means 10 months is middle‐age; whether the GH effect would continue in older mice, or produce full “aged” phenotype (e.g., functional decline, histology) is less clear. Also, the transcriptome overlap is 596 shared DEGs, which is meaningful but still a small fraction of the full set ~4 k.
  6. Lack of in‐depth mechanistic intervention: The study points at transcription factors (e.g., PPAR-α, SREBF1, CLOCK) and oxidative/glycation stress, but does not deeply interrogate e.g., how GH overexpression leads to higher AGE formation: is it via higher glucose/glycolysis flux, decreased detoxification, increased methylglyoxal production, etc? A path from GH → metabolic fluxes → glycation → damage would require more mechanistic work.
  7. Absence of lifespan/long-term endpoints: While metabolic and motor/strength parameters improve with intervention, the study does not report on lifespan extension or full healthspan metrics (e.g., tumour incidence, liver histology, fibrosis, regenerative capacity). For ageing research, functional/histological endpoints matter.
  8. Potential confounders: GH excess likely changes many things (growth rate, body size, lean/fat composition, IGF-1 levels, insulin sensitivity). Some changes may reflect the growth phenotype rather than “accelerated ageing”. The authors discuss this but disentangling growth/stress vs accelerated ageing is complex.

Implications & Recommendations for Your Domain (Longevity / Healthspan)

Given your interest in longevity, healthspan, and metabolic/biomarker optimization, the key take-aways:

  • This paper supports the concept that endocrine dysregulation (e.g., GH excess) can accelerate an ageing‐like state in an organ (liver) via metabolic/inflammatory/glycation stress.
  • It suggests that interventions targeting glycation (AGEs) might mitigate part of the ageing phenotype—this is relevant for you if you are considering supplement/diet/clinical translation approaches (though the cocktail used is high‐dose and preclinical).
  • For biomarker work: AGE levels (e.g., CML, MGH-1) might be considered as candidate biomarkers of metabolic/organ stress in longevity protocols.
  • For clinical/entrepreneurial translation: If you explore anti-glycation interventions (dietary, pharmacological) you might consider organ‐specific assessments (e.g., liver function, hepatic transcriptomic/metabolic signatures) especially in conditions of GH/IGF dysregulation.
  • But: the translational leap to humans must be cautious. Instead of thinking “GH excess causes ageing” as a universal mechanism, interpret this as “in certain pathological states (GH excess) there is accelerated ageing via glycation/inflammation; similar mechanisms may be operative in other contexts (metabolic syndrome, non-alcoholic fatty liver disease) but need direct evidence.”
  • If you pursue interventions, rigorous mechanistic understanding and human dosing/safety is required—especially because the cocktail included nicotinamide at high per-kg levels, which in humans may have side effects.

Verdict

Overall, this is a strong, well-executed study that adds meaningful insight into how GH excess might accelerate ageing in liver via glycation and inflammation. For a longevity specialist like you, the translational angle (glycation lowering) is especially interesting. That said, caution is needed: the model is pathological (GH excess) rather than normative ageing, the intervention uses high doses, and lifespan/organ‐level functional outcomes are still missing. I would regard this as supportive evidence that glycation stress is a modifiable axis of liver ageing, rather than definitive proof that GH axis modulation should become a standard longevity intervention.

#3

Actionable Insights from the above paper:

Below is a concise, evidence-grounded extraction of actionable insights from the GH-excess/glycation–liver-aging study, filtered through what is actually translationally plausible for human health and longevity. These are not clinical recommendations, but mechanistic findings that can inform health-optimization strategies.

Actionable Insights for Health & Longevity

1. Glycation burden (AGEs) is a modifiable driver of metabolic and hepatic aging

The study demonstrates that excessive glycation—specifically AGE accumulation such as CML and MGH-1—tracks closely with liver inflammation, metabolic dysfunction, and accelerated aging signatures.
Actionable takeaway:

  • Reducing glycation stress is a legitimate target for slowing metabolic and hepatic aging.
  • This aligns with existing human evidence linking AGEs with diabetes, NAFLD, cognitive decline, and vascular aging.

Practical levers (supported by human studies):

  • Avoid high-temperature cooking (grilling, frying, broiling)—major contributor to exogenous AGEs.
  • Maintain tight post-meal glucose control (post-prandial spikes significantly raise endogenous glycation flux).
  • Prioritize diets lower in AGE-dense foods (processed meats, seared meats, baked/fried carbs).

2. Compounds that lower glycation or methylglyoxal may protect liver function

The “Gly-Low” cocktail partially reversed GH-driven liver aging signatures and restored metabolic markers. While the doses used were supra-physiologic for humans, the mechanisms are relevant and several components have human data:

Components with plausible translational value:

  • Alpha-lipoic acid: supports glutathione redox cycling, reduces glyoxal/MGO formation in human trials.
  • Thiamine / Benfotiamine: reduces formation of AGEs via transketolase activation; used in diabetes complications and neuropathy.
  • Pyridoxamine: a known AGE-inhibitor; previously in clinical trials for diabetic nephropathy (safe but unapproved).
  • Nicotinamide / NAD+ precursors: boost NAD(P)H pools, enhance detoxification of reactive carbonyl species.

Actionable takeaway:
Strategic use of anti-glycation compounds—especially thiamine/benfotiamine and alpha-lipoic acid—has mechanistic and some clinical support for reducing glycation load, independent of the GH pathway.

3. The liver is disproportionately sensitive to chronic metabolic and endocrine stress

GH excess is a pathological model, but the mechanistic insight generalizes:

  • Excess substrate load → high glycolytic flux → methylglyoxal → AGEs → inflammation → transcriptomic aging.

This is analogous to human conditions such as:

  • insulin resistance
  • metabolic syndrome
  • visceral adiposity
  • chronic overnutrition

Actionable takeaway:
Interventions reducing hepatic metabolic load will reduce glycation acceleration and hepatic aging:

  • Maintain low post-prandial glucose variability.
  • Minimize fructose burden (fructose dramatically accelerates methylglyoxal formation in hepatocytes).
  • Maintain liver fat < 5% (via caloric deficit, exercise, or GLP-1/SGLT2 if clinically appropriate).

4. Improving redox balance is likely protective against glycation-driven aging

The study shows that:

  • GH-excess → lower reduced glutathione (GSH/GSSG ratio), lower NADPH
  • Gly-Low → partial restoration of redox capacity

Actionable takeaway:
Support for maintaining high hepatic redox capacity:

  • Resistance training and endurance exercise increase glutathione turnover and NADPH generation.
  • Diets rich in sulfur amino acids (cysteine, taurine) support glutathione biosynthesis.
  • Minimizing chronic oxidative stress (e.g., smoking, chronic alcohol intake) appears especially relevant for glycation control.

5. Glycation is upstream of inflammation and transcriptomic aging

The study’s RNA-seq results show that glycation stress drives:

  • immune activation
  • complement signaling
  • downregulation of lipid/FA oxidation
  • circadian gene disruption (CLOCK, PPAR-α)

This suggests:
Reducing glycation burden can change transcriptional programs that are characteristic of liver aging.

Actionable takeaway:
Glycation control isn’t only about glucose or diabetes prevention—it’s an upstream knob that modulates systemic aging pathways (mitochondrial oxidation, circadian regulation, lipid handling).

6. Screening and tracking AGEs may become an early-aging biomarker

The authors highlight reproducible increases in specific AGEs (CML, MGH-1).

Actionable takeaway for longevity practitioners:

  • Skin autofluorescence AGE readers (already in diabetology) may serve as early-aging biomarkers.
  • Research-grade serum AGEs (CML, CEL, pentosidine) could be added to advanced biomarker panels.
  • High AGE load signals a need to address diet, glucose handling, and hepatic metabolic stress.

7. The GH/IGF-1 axis matters—both too high and too low are undesirable

The study reinforces earlier findings:

  • GH excess accelerates aging.
  • GH/IGF-1 deficiency extends lifespan in mice.

But in humans the relationship is U-shaped, and low IGF-1 is associated with frailty, sarcopenia, and mortality.

Actionable takeaway:
Target a physiologic IGF-1 range.
Avoid chronic GH/IGF-1 elevation from:

  • overfeeding
  • anabolic misuse
  • uncontrolled testosterone/GH secretagogues
  • high-protein feeding late at night

8. Glycation control is potentially synergistic with metabolic longevity strategies

Because glycation is downstream of glucose and oxidative stress, insights integrate with existing frameworks:

Synergy:

  • GLP-1s / SGLT2 inhibitors → lower glucose exposure → reduce glycation flux
  • Time-restricted feeding → reduced post-prandial glycation
  • Metformin / acarbose → lower glycemic excursions → fewer AGEs
  • Regular endurance exercise → increases glyoxalase activity and mitochondrial detoxification

High-Probability, Real-World Applications

If forced to prioritize the insights into practical value for human longevity:

  1. Control post-prandial glucose excursions (lowest-hanging fruit for reducing glycation exposure).

  2. Use AGE-lowering compounds with human data:

    • Benfotiamine
    • Alpha-lipoic acid
    • Pyridoxamine (where legally accessible)

  3. Limit dietary AGEs from cooking methods (a real effect size in human studies).

  4. Reduce hepatic substrate load:

    • Lower fructose intake
    • Lower visceral fat
    • Improve insulin sensitivity

  5. Support redox capacity (glutathione, NADPH, sulfur amino acids).

  6. Track glycation markers as part of a longevity biomarker panel.