J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

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Review

Volume 17, Number 9, October 2025, pages 469-489

Adenosine Monophosphate-Activated Protein Kinase Activation and Mammalian Target of Rapamycin Complex 1 Inhibition: A Mechanistic Rationale for Anti-Aging Therapy in Type 2 Diabetes

Figure 2. Effects of AMPK activation and mTOR inhibition on aging-related molecules and aging hallmarks. Thick gray arrows indicate effects, and red upward arrows indicate the increase, and blue downward arrows indicate the decrease. AGEs: advanced glycation end products; AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; NAD⁺: nicotinamide adenine dinucleotide; NLRP3: nod-like receptor pyrin 3 inflammasome; Nrf2: nuclear factor E2-related factor 2; NF-κB: nuclear factor-kappa B; PGC1α: peroxisome proliferator-activated receptor-γ coactivator 1α; ROS: reactive oxygen species; SIRT1: sirtuin 1; ULK1: unc-51-like autophagy activating kinase 1.

**Table 1.** Effects of Nutritional Interventions That Improve Aging Hallmarks by AMPK Activation and mTORC1 Inhibition on Type 2 Diabetes
Therapeutic interventions	AMPK activation	mTORC1 inhibition	Effects on type 2 diabetes
AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; PUFA: polyunsaturated fatty acids; TG: triglyceride; HbA1c: glycated hemoglobin.
Calorie restriction	(+) [201]	(+) [202]	The meta-analysis showed that calorie-restricted diets were an effective intervention for type 2 diabetes remission in comparison to a usual diet or usual care [203].
Vitamin E	(+) [204]	(+) [205]	The meta-analysis showed that vitamin E intake has a beneficial role in improving HbA1c and insulin resistance in a population with diabetes [206].
Vitamin C	(+) [207]	(+) [208]	The meta-analysis showed that long-term (≥ 12 weeks) and high-dose vitamin C supplementation (≥ 1,000 mg/d) ameliorated glycemic profile in patients with type 2 diabetes [209].
Resveratrol	(+) [210]	(+) [211]	In the meta-analysis, there was a significant effect on the reduction of insulin resistance and glycated hemoglobin. For fasting blood glucose, the results were significant for individuals with diabetes [212].
Astaxanthin	(+) [213]	(+) [213]	Astaxanthin showed preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects [214].
n3-PUFA	(+) [215]	(+) [216]	An individual participant-level pooling project of 20 prospective cohort studies showed that higher circulating biomarkers of seafood-derived n-3 PUFA were associated with lower risk of type 2 diabetes in a global consortium of prospective studies [217].

Table 1. Effects of Nutritional Interventions That Improve Aging Hallmarks by AMPK Activation and mTORC1 Inhibition on Type 2 Diabetes

Therapeutic interventions

AMPK activation

mTORC1 inhibition

Effects on type 2 diabetes

AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; PUFA: polyunsaturated fatty acids; TG: triglyceride; HbA1c: glycated hemoglobin.

Calorie restriction

(+) [201]

(+) [202]

The meta-analysis showed that calorie-restricted diets were an effective intervention for type 2 diabetes remission in comparison to a usual diet or usual care [203].

Vitamin E

(+) [204]

(+) [205]

The meta-analysis showed that vitamin E intake has a beneficial role in improving HbA1c and insulin resistance in a population with diabetes [206].

Vitamin C

(+) [207]

(+) [208]

The meta-analysis showed that long-term (≥ 12 weeks) and high-dose vitamin C supplementation (≥ 1,000 mg/d) ameliorated glycemic profile in patients with type 2 diabetes [209].

Resveratrol

(+) [210]

(+) [211]

In the meta-analysis, there was a significant effect on the reduction of insulin resistance and glycated hemoglobin. For fasting blood glucose, the results were significant for individuals with diabetes [212].

Astaxanthin

(+) [213]

Astaxanthin showed preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects [214].

n3-PUFA

(+) [215]

(+) [216]

An individual participant-level pooling project of 20 prospective cohort studies showed that higher circulating biomarkers of seafood-derived n-3 PUFA were associated with lower risk of type 2 diabetes in a global consortium of prospective studies [217].

**Table 2.** Effects of Anti-Diabetic Drugs That Have AMPK-Activating and mTORC1-Inhibitory Effects on Aging-Related Diseases
Anti-diabetic drugs	Effects on CVD	Effects on AD
AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; AD: Alzheimer’s disease; aHR: adjusted hazard ratio; CI: confidence interval; CVD: cardiovascular disease; GLP-1RAs: glucagon-like peptide-1 receptor agonists; OR: odds ratio; SGLT2is: sodium-glucose cotransporter 2 inhibitors; 3P-MACE: 3-point major cardiovascular event.
Metformin	A meta-analysis showed that the risk of CVD mortality in metformin patients was lower than in the other two groups (placebo and other anti-diabetic drugs) (OR: 0.771; 95% CI: 0.688 to 0.853), and the risk of CVD in metformin users was also lower than in the other two groups (OR: 0.828; 95% CI: 0.781 to 0.785) [221].	A meta-analysis of 10 clinical observational studies showed no significant association between AD incidence and metformin exposure (OR: 1.17; 95% CI: 0.88 to 1.56) [222]. Three relevant clinical trials, Metformin in Alzheimer’s Dementia Prevention (MAP), MET-FINGER, MET-MEMORY, are currently underway to understand the effect of metformin on the prevention of AD [223].
SGLT2is	The EMPA-REG OUTCOME showed that empagliflozin reduced 3P-MACE by 14% as compared with placebo [224]. The CANVAS program showed that the rate of 3P-MACE was lower with canagliflozin as compared with placebo by 14% [225].	A retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes showed that SGLT2is use was associated with reduced risks of AD (aHR: 0.81; 95% CI: 0.76 to 0.87) [226].
GLP-1RAs	The LEADER showed that 3P-MACE occurred in significantly fewer patients in the liraglutide group than in the placebo group (HR: 0.87; 95% CI: 0.78 to 0.97) [227]. The SUSTAIN-6 trial showed that 3P-MACE occurred in 108 of 1,648 patients (6.6%) in the semaglutide group and in 146 of 1,649 patients (8.9%) in the placebo group (HR: 0.74; 95% CI: 0.58 to 0.95) [228].	The meta-analysis of pre-clinical studies showed that GLP-1RAs improved the learning and memory abilities of AD rodents; GLP-1RAs reduced amyloid beta deposition and phosphorylated tau levels in the brains of AD rodents [229]. A meta-analysis of human studies also showed that GLP-1RAs effectively improved cognitive function in patients with AD [230].

Table 2. Effects of Anti-Diabetic Drugs That Have AMPK-Activating and mTORC1-Inhibitory Effects on Aging-Related Diseases

Anti-diabetic drugs

Effects on CVD

Effects on AD

AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; AD: Alzheimer’s disease; aHR: adjusted hazard ratio; CI: confidence interval; CVD: cardiovascular disease; GLP-1RAs: glucagon-like peptide-1 receptor agonists; OR: odds ratio; SGLT2is: sodium-glucose cotransporter 2 inhibitors; 3P-MACE: 3-point major cardiovascular event.

Metformin

A meta-analysis showed that the risk of CVD mortality in metformin patients was lower than in the other two groups (placebo and other anti-diabetic drugs) (OR: 0.771; 95% CI: 0.688 to 0.853), and the risk of CVD in metformin users was also lower than in the other two groups (OR: 0.828; 95% CI: 0.781 to 0.785) [221].

A meta-analysis of 10 clinical observational studies showed no significant association between AD incidence and metformin exposure (OR: 1.17; 95% CI: 0.88 to 1.56) [222]. Three relevant clinical trials, Metformin in Alzheimer’s Dementia Prevention (MAP), MET-FINGER, MET-MEMORY, are currently underway to understand the effect of metformin on the prevention of AD [223].

SGLT2is

The EMPA-REG OUTCOME showed that empagliflozin reduced 3P-MACE by 14% as compared with placebo [224]. The CANVAS program showed that the rate of 3P-MACE was lower with canagliflozin as compared with placebo by 14% [225].

A retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes showed that SGLT2is use was associated with reduced risks of AD (aHR: 0.81; 95% CI: 0.76 to 0.87) [226].

GLP-1RAs

The LEADER showed that 3P-MACE occurred in significantly fewer patients in the liraglutide group than in the placebo group (HR: 0.87; 95% CI: 0.78 to 0.97) [227]. The SUSTAIN-6 trial showed that 3P-MACE occurred in 108 of 1,648 patients (6.6%) in the semaglutide group and in 146 of 1,649 patients (8.9%) in the placebo group (HR: 0.74; 95% CI: 0.58 to 0.95) [228].

The meta-analysis of pre-clinical studies showed that GLP-1RAs improved the learning and memory abilities of AD rodents; GLP-1RAs reduced amyloid beta deposition and phosphorylated tau levels in the brains of AD rodents [229]. A meta-analysis of human studies also showed that GLP-1RAs effectively improved cognitive function in patients with AD [230].