A mitochondrial protein may hold the secret to longevity, new study finds

As life expectancy continues to climb globally, the focus of many people has moved from longevity alone to living in good health. This has drawn attention to the need to extend “healthspan,” the period during which an individual maintains their vitality, independence, and good health, and is free from major age-related issues. Mitochondria, known popularly as the powerhouse of the cell, are central to this goal as they produce the energy essential for life in the form of adenosine triphosphate (ATP). Given that many age-related diseases and aging itself are strongly linked to the decline of mitochondrial function, mitochondria is a prime target for research aimed at extending healthy longevity.

Mitochondrial energy production relies on compounds known as respiratory chain complexes, which facilitate proton and electron transfers, necessary for generating ATP. Scientists have long known that these complexes can group together into dynamic higher-order assemblies called supercomplexes, which are believed to boost respiratory efficiency. However, the evidence for a clear and causal link between these supercomplexes and direct health benefits is quite limited, especially in animal models.

To address this knowledge gap, a research team led by Team Leader Satoshi Inoue from the Tokyo Metropolitan Institute for Geriatrics and Gerontology in Japan, investigated the role of COX7RP, a mitochondrial protein involved in the formation of supercomplexes. Their latest study on this topic, co-authored by Dr. Kazuhiro Ikeda from Saitama Medical University in Japan, was published online in the journal Aging Cell on November 18, 2025.

“We previously identified COX7RP, a mitochondrial protein, as a key factor that promotes the formation of mitochondrial respiratory supercomplexes, thereby enhancing energy production and reducing reactive oxygen species (ROS) that cause oxidative stress in cells,” explains Dr. Inoue. “Based on this, we investigated the role of COX7RP and mitochondrial respiratory supercomplexes in regulating aging and anti-aging processes.”

The research team developed COX7RP-transgenic (COX7RP-Tg) mice models that were genetically engineered to express higher levels of COX7RP throughout their life. This enabled the researchers to test the protein’s impact on longevity, aging, and metabolism with great detail.

Surprisingly, the COX7RP-Tg mice exhibited a significantly prolonged lifespan, with the average lifespan being 6.6% higher than that of wild-type mice. Beyond longevity, these transgenic mice also demonstrated numerous health benefits, suggesting an extension of their healthspan as well. In particular, the team observed improved glucose homeostasis through enhanced insulin sensitivity, along with healthier lipid profiles with reduced blood triglycerides and total cholesterol. Additional benefits included enhanced muscle endurance and lower fat accumulation in the liver.

At the cellular level, the researchers further confirmed that COX7RP significantly improved mitochondrial performance. Tissues from the COX7RP-Tg mice showed increased formation of mitochondrial respiratory supercomplexes, leading to the production of higher levels of ATP. Notably, a detailed analysis of white adipose tissue showed improvements in various aging-related biomarkers, such as higher levels of coenzyme NAD⁺ and lower levels of ROS, and the cellular aging marker β-galactosidase. Additionally, with single-nucleus RNA sequencing on white adipose tissue of older mice, the team revealed lower expression of genes linked to age-related inflammatory responses, particularly genes related to the senescence-associated secretory phenotype (SASP), a prototypic characteristic of senescent cells.

Together, these findings suggest that increasing the energy efficiency of mitochondria can delay and mitigate problems associated with aging. “Our study elucidated novel mitochondrial mechanisms underlying anti-aging and longevity, and provided new insights into strategies for promoting healthspan and extending lifespan,” highlights Dr. Inoue. “For instance, supplements and medications that enhance the assembly and function of mitochondrial respiratory supercomplexes may contribute to longevity expansion.”

Future studies on this topic could help establish mitochondrial supercomplexes as promising therapeutic targets and pave the way for novel interventions aimed at maintaining vitality and addressing age-related metabolic diseases such as diabetes, dyslipidemia, and obesity.

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Reference
DOI: 10.1111/acel.70294

About Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG), Japan
The Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG) is a premier research institute in Tokyo, Japan, dedicated to addressing the challenges of an aging society. Established in 1972 and reorganized in 2009, TMIG integrates clinical and basic research to promote healthy aging and improve the quality of life of individuals and the aging society. With over 250 researchers from diverse fields, including biology, medicine, public health, and social sciences, TMIG leads innovative projects such as the Healthy Aging Innovation Center and the Integrated Research Initiative for Living Well with Dementia. Guided by strategic vision of the Tokyo Metropolitan Assembly, TMIG is dedicated to advancing geriatric care by shifting the focus from curative to supportive medicine. Through interdisciplinary research and practical innovation, TMIG remains committed to addressing age-related challenges and making meaningful contributions to society.

Know more, here: https://www.tmghig.jp/research/en/

About Team Leader Satoshi Inoue from Tokyo Metropolitan Institute for Geriatrics and Gerontology (TMIG), Japan
Dr. Satoshi Inoue leads a research group at the Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute for Geriatrics and Gerontology. He specializes in genetics, genomics, cancer, molecular glycobiology, proteomics, and mitochondrial processes and their relationship with aging and disease. He has over 140 publications to his name.

Funding information
This work was supported by grants of the Japan Society for the Promotion of Science (23K07996, 24K02505, 22K06929, 23H02962, 24K21297); the Integrated Research Initiative for Living Well with Dementia at the Tokyo Metropolitan Institute for Geriatrics and Gerontology; the Takeda Science Foundation; and the Vehicle Racing Commemorative Foundation. This research was also supported by AMED under Grant Number JP25gm2110001.