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

Timing the AIDS pandemic and why it made history (Part II)

In Part I of this post I discussed the Science paper that proved HIV was the result of a cross-transmission from chimpanzees to humans. In that paper, Hahn et al. conclude with an open question:

"The timing of SIVcpz transmission to humans, leading ultimately to the HIV-1 pandemic, has been a challenging question. We know from analyses of stored samples that humans in west central Africa had been infected with HIV-1 group M viruses by 1959 and with group O viruses by 1963. But how much earlier were these viruses introduced into the human population? [...] It should be possible to estimate the timing of the onset of the pandemic by calculating the date of the last common ancestor of HIV-1 group M."

In a phylogenetic tree (see the definition I gave last time), the last common ancestor is the root of the tree: that's the "patriarch" of the sample if you will, the one sequence from which, one divergent event at the time, the whole sample originated. Phylogenetic analyses allow us not only to reconstruct the evolutionary history of the sequences, but also, if you have a rough idea of what the mutation rate is (i.e. how often new mutations arise) to time them. It's a technique often referred to as "molecular clock," which originated from the observation that the number of molecular differences between different lineages increases linearly with time and that substitutions accumulated according to a Poisson distribution.

Korber et al. used parallel computers to apply maximum-likelihood tree-building methods to the envelope sequences (the envelope is one of the HIV genes) from 159 individuals. They note:

"Although it is unrealistic to expect that HIV-1 evolution will always rigidly adhere to a molecular clock, it is, however, the average behavior of many sequences that we consider here, and our control estimates of known times were accurate."

To this they combined another data point: the year of sampling of the sequences used to reconstruct the tree.

(A) The phylogenetic tree used for the calculation. (B) The branch lengths from the tree plotted versus the year of sampling an dprojected backwards in time.

Once they reconstructed the phylogenetic tree, with the root sitting more or less in the middle, and thus at the same distance from the various HIV subgroups (the clusters marked with capital letters in panel A above), they plotted the branch lengths of the tree against time (panel B) and did a linear fit to extrapolate the time since the last common ancestor: 1931, with a 95% confidence interval of 1915 to 1941. Furthermore, testing a known HIV-1 group M isolate from 1959 gave an accurate estimate for the date of its origin, indicating that the assumptions of the method are reasonable.

Notice that 1931 marks the year the first HIV-1 lineage, the M-group, started to spread and diversify in humans. It does not tell us whether or not the virus was transmitted at the same time as it started to diversify. It could be possible that the virus cross-transmitted to humans earlier and remained isolated within a small population. Around the '30s socioeconomic changes would've allowed the spread of the virus:

"Strictly speaking, our estimate is neither an upper nor a lower bound on the date of the actual zoonosis. Rather, it is the approximate time of the bottleneck event that was the genesis of the M group and captures the moment of the beginning of the expansion of the M group. If the M group originated in humans, then this would date the founder virus of the pandemic."

Another important question is addressed in the following commentary by David Hillis:

"If HIV has been present in human populations since at least the 1930s (and probably much earlier), why did AIDS not become prevalent until the 1970s? The phylogenetic trees of HIV-1 indicate that the spread of the virus was initially quite slow‚ by 1950 there existed 10 or fewer HIV-1 M-group lineages that left descendants that have survived to the present. The epidemic exploded in the 1950s and 1960s, coincident with the end of colonial rule in Africa, several civil wars, the introduction of widespread vaccination programs (with the deliberate or inadvertent reuse of needles), the growth of large African cities, the sexual revolution, and increased travel by humans to and from Africa. Given the roughly 10-year period from infection to progression to AIDS, it was not until the 1970s that the symptoms of AIDS became prevalent in infected individuals in the United States and Europe."

B. Korber, M. Muldoon, J. Theiler, F. Gao, R. Gupta, A. Lapedes, B. H. Hahn, S. Wolinsky, and T. Bhattacharya. (2000). Timing the Ancestor of the HIV-1 Pandemic Strains Science, 288 (5472), 1789-1796 DOI: 10.1126/science.288.5472.1789