The Mitochondrial Free Radical Theory of Aging

Theories of aging

The Mitochondrial Free Radical Theory of Aging (MFRTA) is one of the leading theories of how aging occurs on a biological level. Defining the molecular events and the pathways of aging are still contentious in the study of biology and medicine. Theories fall into a couple of primary categories - programmed aging and increasing errors in biological processes.1

Programmed theories of aging:

Programmed Longevity

  • Genetic differences underlie the majority of age-related deficits and differences in individual's DNA drives differences in lifespan.

Endocrine Theory

  • Aging is regulated by hormone related signaling, particularly metabolic and growth-related pathways: i.e. insulin/IGF-1.

Immunological Theory

  • The decline of the immune system over time leads to a reduced ability to fight infections, leading to accumulating damage.
  • This theory is supported by evidence that certain facets of the immune system become less effective over time, i.e. antibody-based immunity declines over time.

Damage or Error Theories of aging:

Wear and Tear Theory

  • Environmental stress causes progressive damage to biological processes and structures

Rate of Living Theory

  • The greater an organism's rate of metabolism the faster the rate of aging.

Cross-linking theory

  • Cross-linking reactions, linking different biological molecules together, occurs with increasing frequency as an organism ages and directly results in cellular aging.

Somatic DNA Damage Theory

  • Damage to DNA occurs all the time, but the healthy cell can correct these errors. This theory postulates that these error correction processes become less effective as one age.

Free Radicals Theory / Mitochondrial Free Radical Theory

  • Free radical molecules accumulate over time and begin to damage cellular proteins and DNA.
  • Mitochondria are the main cellular producers of free radical compounds, so the theory arose that mitochondria are the main cellular targets of reactive oxygen species.
  • Put forth by Aubrey de Grey; the mitochondrial proliferation hypothesis is that mitochondria damaged by free radicals may proliferate more than functioning mitochondria.

It's likely that some or all of these theories act in the combinatorial fashion to contribute to human aging. In cell and animal models, various interventions that seem to increase lifespan have been viewed in the context of these theories. In particular caloric restriction, and NAD/sirtuin-based biological pathways.2

Exploring mitochondrial function during aging and the mitochondrial proliferation hypothesis

Since 1956, the free radical hypothesis of aging has suggested that aging may be driven by biological stress and damage that accumulates through free radical molecules. Free radicals are compounds that have an excess of electrons, which can readily react with surrounding molecules. These reactions result in molecular damage to proteins, lipids, and other molecules that make up cells.3

freerads Figure 1. Compounds that are free radicals or can break down into free radical components

In 1997, Aubrey de Grey postulated that differences in mitochondrial proliferation are a major driver of aging. This theory is based on the fact that mitochondria are the site of oxygen based metabolism, and produce many free radicals during this process. Metabolically effective mitochondria produce many free radicals, and if these mitochondria are damaged by them, the cell will clear them out. The cell has mechanisms to clear out defective mitochondria (called the lysosome degradation pathway). However, if certain mitochondria are damaged in their metabolic ability, and generate fewer free radical, but are not identified as defective and destroyed by the cell, they will proliferate. Thus, if these defective mitochondria proliferate within the cell, they will crowd out the more functional mitochondria. And this crowding out is directly leading to cellular aging.4


Figure 2. Mitochondria diagram

Pros and Cons of the mitochondrial proliferation hypothesis

For the most part, there is strong evidence supporting a link between mitochondrial free radical action, and aging at the level of the cell and the organism.5,6Specifically:

  • Mitochondrial free radical production is negatively correlated with longevity in mammals.
  • Dietary restriction/caloric restriction (which has been shown to have longevity benefits from single cells yeast all the way to primates), results in reduced mitochondrial free radical production
  • The increase of mitochondrial anti-oxidant enzymes causes an increase in mean life span in mice.

However, at present de Grey's theory is as yet unsubstantiated. There hasn't been any data to demonstrate that defective mitochondria accumulate to any great degree, compared to healthy mitochondria.

Editorial Opinion

The mitochondrial free radical theory of aging is well-substantiated and has been developed over the past 50-60 years. However, specifics of the mechanism underlying reactive oxygen species, mitochondrial function, and mitochondrial proliferation, are not fully worked out. In particular, experiments that draw a direct link between mitochondrial free-radical levels/damage, and cell clearance of defective mitochondria, need to be carried out.

Recently we sat down with Aubrey de Grey to discuss his theories and his life's mission to combat aging. Check out the Thinking Podcast on SoundCloud and Youtube.

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