Highlight
– Henagliflozin treatment significantly increased telomere length, a key biomarker of cellular aging, in patients with type 2 diabetes.
– The drug elevated insulin-like growth factor-binding protein-3 (IGFBP-3) and β-hydroxybutyrate levels, indicative of beneficial metabolic modulation.
– Enhanced cytotoxic T lymphocyte (CTL) function was evidenced by increased granzyme B expression, suggesting improved immune surveillance.
– Metabolomic profiling revealed upregulation of thiamine levels and metabolism, pointing to multiple pathways of potential anti-aging effects.
Study Background and Disease Burden
Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder characterized by chronic hyperglycemia, metabolic dysregulation, and increased risk of micro- and macrovascular complications. Aging is a major risk factor for T2DM, and conversely, diabetes accelerates biological aging processes, contributing to adverse health outcomes and reduced lifespan. Effective interventions addressing both glycemic control and aging mechanisms remain an unmet need.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent a novel class of glucose-lowering agents that reduce renal glucose reabsorption, leading to glucosuria and improved glycemic parameters. Beyond glucose control, SGLT2 inhibitors have been hypothesized to mimic caloric restriction effects—an established anti-aging intervention—in preclinical models. Caloric restriction mimetics induce metabolic and cellular changes that prolong healthspan. However, clinical data regarding their impact on biomarkers of aging have been sparse.
This study investigated henagliflozin, a potent SGLT2 inhibitor, assessing its effects on established and exploratory aging biomarkers in patients with T2DM, thereby exploring its potential as an anti-aging therapeutic option in this population.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled clinical trial conducted across various centers in China. A total of 150 adult individuals diagnosed with type 2 diabetes were enrolled and randomized in a 1:1 ratio to receive either oral henagliflozin at a dose of 10 mg once daily or matching placebo.
The intervention period lasted 26 weeks, during which participants continued their standard diabetes care under supervision. The primary endpoint was change in telomere length, a canonical marker of cellular senescence and aging. Secondary endpoints included changes in insulin-like growth factor-binding protein-3 (IGFBP-3), β-hydroxybutyrate (a ketone body linked to metabolic health), glucose metabolism parameters, immune cell function, and metabolomic profiles.
Safety assessments were performed regularly to monitor adverse events and laboratory parameters.
Key Findings
The study revealed multiple significant effects of henagliflozin compared to placebo.
1. Telomere Length Extension: Patients receiving henagliflozin showed a statistically significant increase in telomere length after 26 weeks, suggesting a potential deceleration of cellular aging. This represents a novel clinical finding linking SGLT2 inhibition with cellular longevity.
2. Metabolic Improvements: Along with enhanced glycemic control, henagliflozin increased serum levels of IGFBP-3 and β-hydroxybutyrate. IGFBP-3 plays a role in modulating insulin-like growth factor signaling, implicated in aging processes. β-hydroxybutyrate elevation indicates a shift towards favorable metabolic pathways akin to caloric restriction or ketogenic states.
3. Immune Modulation: Immune cell analyses demonstrated a significant increase in granzyme B expression in cytotoxic T lymphocytes (CTLs), with trends toward increased perforin expression in CTLs and total T lymphocytes. Granzyme B and perforin are critical effectors of cell-mediated cytotoxicity, which declines with age. These findings suggest henagliflozin may restore or enhance immune surveillance mechanisms compromised in aging and diabetes.
4. Metabolomic Changes: Broad untargeted metabolomic profiling identified significant alterations in metabolite concentrations associated with henagliflozin treatment. Notably, thiamine (vitamin B1) levels increased, with pathway analysis indicating enhanced thiamine metabolism. Thiamine is essential for mitochondrial function and energy metabolism, underscoring potential mechanisms by which henagliflozin exerts systemic anti-aging effects.
5. Safety: Henagliflozin was well-tolerated, with adverse event profiles consistent with its known safety in diabetes management. No new safety signals were observed.
Expert Commentary
This rigorously designed trial offers the first compelling clinical evidence that henagliflozin, beyond its glucose-lowering properties, positively modulates multiple aging biomarkers in patients with type 2 diabetes. The increase in telomere length is particularly noteworthy, as telomere attrition is closely linked with cellular senescence, genomic instability, and age-related disease susceptibility.
Enhancement of CTL cytotoxic function through increased granzyme B and perforin expression addresses a key facet of immune aging (immunosenescence), which contributes to infection risk and possibly oncogenesis in the elderly.
Metabolomic shifts, especially toward enhanced thiamine metabolism, point to mitochondrial and metabolic rejuvenation, supporting biological plausibility. SGLT2 inhibitors’ known promotion of mild ketogenesis (indicated here by β-hydroxybutyrate rise) further aligns with caloric restriction mimetic effects, confirming and expanding preclinical hypotheses.
Limitations include the 26-week duration, which, while adequate to detect biomarker changes, does not confirm long-term clinical outcomes related to aging or longevity. Larger, longer trials will be needed to establish whether these biomarker improvements translate into reduced morbidity or mortality.
Additionally, the study population comprised type 2 diabetic patients; implications for non-diabetic populations remain speculative.
Conclusion
Henagliflozin demonstrates promising anti-aging properties in patients with type 2 diabetes by improving telomere length, enhancing beneficial metabolic markers, and modulating immune effector functions. These multi-pathway effects reinforce the paradigm of SGLT2 inhibitors as not only glucose-lowering agents but also potential caloric restriction mimetics with broader healthspan benefits.
This trial provides a strong rationale for further investigation into the role of SGLT2 inhibitors in aging-related interventions and supports their integrated use in metabolic disease management with a focus on healthy aging.
Future research should aim to longitudinally validate these findings in diverse populations and explore mechanistic pathways in greater depth.
References
Zhang J, Cai W, Liu D, Zheng N, Wang Y, Qiu F, Zheng H, Gan H, Huang Y, Zhou Y, Yu M, Xiong S, Luo G, Guo J, Zhu L, Zhang Y, Ke H, Liu Y, Huang G, Yu C, Li C, Hu L, Xu J. Effect of henagliflozin on aging biomarkers in patients with type 2 diabetes: A multicenter, randomized, double-blind, placebo-controlled study. Cell Rep Med. 2025 Sep 16;6(9):102331. doi: 10.1016/j.xcrm.2025.102331. Epub 2025 Sep 4. PMID: 40912255.
Additional references on SGLT2 inhibitors and aging mechanisms can be found in recent comprehensive reviews in journals such as Diabetes Care and Aging Cell.
