A new hypothesis on the essence of aging — Decreased glycolytic ATP production limits lifespan

A research group including Director Akihiko Taguchi of the Department of Regenerative Medicine Research at the Institute of Biomedical Research and Innovation of the Foundation for Biomedical Research and Innovation at Kobe, in collaboration with the Fraunhofer-Gesellschaft in Germany, announced on March 6 that they have proposed a new hypothesis to explain "why and how aging occurs" through a single factor. The hypothesis states that "the decline in glycolytic ATP production is the fundamental mechanism that causes aging, and only those species that happened to acquire the optimal rate of decline have survived." The results were published in Aging on February 27.

Aging is associated with various disorders and abnormalities, such as mitochondrial damage, DNA damage, abnormal protein accumulation, reduced cell division ability, and telomere shortening. It is believed that aging is caused by these multiple factors, however, the actual nature of the aging process was unknown.

While it was known that glycolytic ATP production gradually decreases with age, the mechanism of how this production declines is not understood. There are many questions that the multi-factor theory cannot explain, such as: "Why do most animals age? Why do aging rates and lifespans differ between species? Why can cancer cells live indefinitely? And why are there species where no signs of aging are observed?"

According to the group, these questions can be explained if the root cause of aging is considered not as multiple factors but as a single factor: the decline in energy production. Specifically, the group proposed the following five-item hypothesis:

1. (i) The decline in glycolytic ATP production is the basic mechanism that limits lifespan.
2. (ii) For an individual, aging caused by the decline in glycolytic ATP production is harmful.
3. (iii) For a species, it is necessary for individuals to age at an appropriate speed to allow for generational turnover, which is required to adapt to environmental changes and ensure species survival.
4. (iv) There is no regulatory mechanism to adjust the aging speed of an individual.
5. (v) In adapting to environmental changes, only species that happened to age at an appropriate speed were able to survive through generational turnover.

This hypothesis could explain many mysteries about aging. Species that do not age cannot adapt to environmental changes because generational turnover does not occur, leading to natural selection. Since there is no mechanism to regulate the aging speed of an individual, it is thought that only species that happened to age at the appropriate speed survived through generational turnover.

The optimal speed for generational turnover varies depending on the environment in which the species is placed. Cancer cells are thought to be capable of maintaining cellular function because they consistently possess high glycolytic ATP production activity. The group aims to verify this hypothesis further and apply it to regenerative medicine to achieve healthy longevity.

Taguchi stated, "Based on this new hypothesis of aging, regenerative medicine for patients with dementia and amyotrophic lateral sclerosis (ALS) has already begun, and we have obtained results that exceed expectations. We believe that treatments using this new perspective will rapidly spread in the future for various age-related diseases that were previously believed to be untreatable. If you are interested, please feel free to contact us!"

Journal Information
Publication: Aging
Title: A decline in glycolytic ATP production is the fundamental mechanism limiting lifespan; species with an optimal rate of decline over time survived
DOI: 10.18632/aging.206356