Debunking myths on genetics and DNA

Friday, January 3, 2014

The secret to a long life? Active mitochondria!

For quite a while now we've known that if we want to live a long, healthy life, we must exercise regularly and be good about what we eat. Recent studies have added another piece to the equation: maintain mitochondrial function.

Mitochondria are organelles found in every cell of our body. They hold a very important function: they provide energy to the cell. Most cellular processes take place using energy stored in a molecule called adenosine triphosphate, or ATP, and most of a cell's supply of ATP is produced in the mitochondria through a process called oxidative phosphorylation. Mitochondria are also the only place outside the nucleus where you can find DNA: human mitochondrial DNA (mtDNA) is circular, and it contains 37 genes. Contrary to nuclear DNA, mitochondrial DNA is not unique to every individual because it is inherited from the mother's side only and, therefore, does not undergo parental genetic recombination.

How do mitochondria fit in the longevity puzzle? Lanza et al. [1] found a progressive decline in mitochondrial DNA abundance in skeletal muscle cells with age. The progressive decline of mitochondrial activity in muscular tissue implies less ATP synthesis, and, therefore, less energy for the cell. In addition, mitochondria play a role in regulating programmed cell death, "a vital mechanism to regulate development, cell numbers, and prevent the accumulation perilous tumor cells." Therefore, it is possible that mitochondria influence the loss of muscular mass associated with aging through upregulation of apoptotic processes. In their review, Lanza and Nair [1] cite studies that have shown that mitochondrial activity is reduced in older adults, though it seems to be preserved across similar activity levels, implying that exercise can slow down and even prevent this progressive loss.
"Mitochondrial DNA copy number decreases with age, which could account for the reduction of mitochondrial gene transcripts and therefore, the proteins encoded by these genes [1]."
Even though it's not clear whether the decline in mitochondrial function is a cause or a consequence of the senile phenotype, there have been some new studies suggesting that mitochondria play a major role in regulating cellular aging, and that restoring mitochondrial function can indeed slow down the aging process.

To understand why this is the case, let's go back to mitochondria's main function: they synthesize ATP through oxidative phosphorylation. Most proteins involved in this process are encoded in the nucleus, though 13 are encoded by genes in the mitochondrial DNA. This implies that in order for oxidative phosphorylation to take place and ATP be produced, the nucleus and the mitochondria have to work together and communicate closely. As we age and lose mitochondrial function, this close network weakens, causing loss of oxidative capacity.

Researchers from Harvard Medical School noticed that though there are 4 different oxidative phosphorylation complexes, the one encoded by exclusively nuclear genes does not decline with age, while the others do. Therefore, they hypothesized that the progressive decline of oxidative activity was due to a decline in mitochondrially encoded genes. This study, a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, was published recently in Cell [2]. In the paper, the authors describe a pathway that regulates mitochondria activity in skeletal muscle cells and show that, by knocking out the pathway in genetically modified mice, they could mimic aging by decreasing mitochondrially encoded oxidative phosphorylation complexes. On the other hand:
"Current dogma is that aging is irreversible. Our data show that 1 week of treatment with a compound that boosts NAD+ levels is sufficient to restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse [2]."
The NAD+ compound the Harvard researchers talk about in their paper is a coenzyme that restores communication between the nucleus and the mitochondria. When levels of mitochondrially encoded mRNA are restored, ensuring that the production of mitochondrial proteins participating in the oxidative phosphorylation complexes is no longer declining, the pathways associated with low-fat diets and high exercise regimens are once again activated.
"All of the main players in the nuclear NAD+-SIRT1-HIF-1a-OXPHOS [oxidative phosphorylation] pathway are present in lower eukaryotes, indicating that the pathway evolved early in life’s history. This pathway may have evolved to coordinate nuclear-mitochondrial synchrony in response to changes in energy supplies and oxygen levels, and its decline may be a conserved cause of aging [2]."
Even more remarkable is that the pathway the researchers found is implicated in cancer tissues, too. So, while it's worth reminding ourselves that aging is NOT a disease (I hate it when I see commercials that tell me they found a "cure" for wrinkles!), there are many age-related diseases, including cancer, that could benefit from these findings. As always, it remains to be seen whether the mouse model is reproducible in higher mammals, but finding and understanding these pathways is indeed a great step forward.

[1] Lanza IR, & Nair KS (2010). Mitochondrial function as a determinant of life span. Pflugers Archiv : European journal of physiology, 459 (2), 277-89 PMID: 19756719

[2] Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, & Sinclair DA (2013). Declining NAD(+) Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell, 155 (7), 1624-38 PMID: 24360282


  1. Fascinating. It will be interesting to see if these findings extrapolate to other mammalian species including humans. I wonder if this implies that other activities beyond the pharmacological approach detailed here could have similar effects. One cannot help but notice that people age at different rates and perhaps this is the reason or one of the reasons why that is so.

    1. Thanks, Carolyn. The pathway described in the paper seems to be active in low-fat diets and high-exercise regimens; also, it is activated in low-calorie regimens, a regimen that in small mammals has been proven to considerably lengthen the life span, though the required reduction in caloric intake seems to be preposterous for humans. So yes, it is definitely achievable through several behavioral routes and not just pharmacologically.

  2. Very interesting. As we were taught, cancer cells "do not use" oxidative phosphorylation, but they relay on glycolysis only. If this is the case, I think this study is also directly linked to cancer as well, right?

    1. It is indeed, Aleksandra, and in fact the authors mention it in the discussion, how these results can possibly enlighten new approaches for cancer treatments. Thank you for bringing that up.


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