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Key Points
- AKG reduced insulin resistance and improved glucose intolerance
- Restored metabolic switching between fuels
- Preserved lean muscle mass
- Increased survival outcomes
Study Overview
Researchers used mice (3.5 weeks old) without the ATM gene (Atm-KO) assigned to either receive
- Dietary: 2% CaAKG mixed into food for 60 days
- IV (Intraperitoneal): 10 mg/kg/day CaAKG for 60 days
"Subsequent experiments which extended the treatment duration to 185 days via the dietary supplementation approach was implemented."
CaAKG Enhanced Metabolic Fuel Switching
CaAKG helped the mice use carbs more effectively as a fuel, something they normally struggled with, by acting as an energy source itself and reducing their need to burn protein for energy.
"CaAKG overcame the challenges related to inefficient utilization of carbohydrates via serving as a biological fuel itself. This treatment concurrently alleviated the reliance on protein."
Fuel-switching capacity also improved.
"...Metabolic profiling conducted at P85 also revealed a more prominent improvement in the switching fuel dependence among the mice undergone dietary supplementation with 2% CaAKG."
Improved Glucose Intolerance and Lean Muscle Preservation
Better metabolic switching supported healthier lean muscle maintenance, the body's most insulin-responsive tissue.
Intraperitoneally treated mice showed impaired glucose tolerance, but this was preserved in the dietary CaAKG group.
"Mice receiving 2% CaAKG through dietary incorporation over the same duration demonstrated more superior blood glucose control outcomes."
Lean-muscle preservation translated into better glucose and insulin measures. Research on lean mass preservation demonstrates why maintaining muscle tissue is fundamental to metabolic healthโskeletal muscle serves as the primary site for glucose disposal and insulin sensitivity, making muscle preservation a critical therapeutic target for metabolic dysfunction.
"The consequent preservation in lean muscle mass, a largest tissue in the body, which is also sensitive to insulin, not only improved the overall glucose tolerance, fasting hyperinsulinemia status), but also the HOMA-IR status."
Long-Term CaAKG Supplementation Enhanced Survival
Extended dietary CaAKG treatment supported healthier growth and lowered mortality in Atm-KO mice.
"Analysis of survival rates revealed a significant reduction in mortality among Atm-KO mice receiving 2% CaAKG from the diet, an improvement likely associated with enhanced overall growth as evidenced by increased body length and greater preservation of lean skeletal muscle mass."
CaAKG Preserved Brain Function and Purkinje Cells
Better metabolic health cascaded into better neurological function.
"These endocrine profile improvements also significantly alleviated the degree of deterioration of coordination and motor function in these mice."
CaAKG also protected insulin-sensing Purkinje cells and supported healthier cerebellar synaptic connections.
"Enhancements in metabolic healthโฆ coupled with the direct impact of CaAKG on glutamine dependence, better preserved the number of insulin-sensing Purkinje cells and their synaptic connections in theโฆ cerebellum."
Conclusion
Across short- and long-term experiments, CaAKG consistently improved the metabolic stability of Atm-KO mice. Dietary CaAKG restored carbohydrate utilization, reducing reliance on protein breakdown and preserving lean muscle, which in turn supported healthier glucose and insulin responses.
These benefits extended beyond to the brain, where CaAKG helped maintain Purkinje cell integrity, motor coordination, and markedly reduced mortality.
Together, these findings show that CaAKG meaningfully strengthened whole-body and neurological resilience in the absence of the ATM gene. Breakthrough research on alpha-ketoglutarate continues to reveal its multifaceted therapeutic potential across aging and metabolic disease, positioning AKG as a versatile intervention that addresses both systemic metabolic dysfunction and tissue-specific pathology.
"Our results also indicate that ฮฑ-KG could be considered as a potential therapeutic target for managing human A-T and other disorders characterized by similar metabolic challenges."
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