Michael Fossel Michael is President of Telocyte

June 20, 2018

Aging and Disease: 2.7 Cell Senescence, Changes In Molecular Turnover, Mitochondria

Filed under: mitochondria,senescent cells,Telomeres — Tags: , , — webmaster @ 9:28 am

Many people assume that mitochondria (and free radicals) lie at the heart of aging or that they are “the cause” of aging. Despite having a central role in aging, the assumption that mitochondria cause aging is both simplistic and – not to put too fine a point on it – is totally at odds with both logic and evidence.

Mitochondria do not cause aging.

This is not to say that mitochondria don’t play a central role in aging cells, but playing a central role is not the same as being the cause nor the same as an overarching explanation for aging, let alone an explanation for age-related disease. By analogy, fevers and elevated white blood cell counts (leukocytoses) play a central role in the clinical presentation of many viral infections, but they neither cause nor explain any viral infection. To describe the presentation of a viral infection, you should include the clinical symptoms and signs, including fevers and high white counts, but while they are an integral part of the process of infection, they don’t cause infection. With that in mind, let’s consider mitochondria, starting with a high-level perspective and then looking at the way mitochondria change in aging cells. In so doing, we will see how mitochondrial aging plays a role in cell aging, but we will also see that mitochondrial aging is secondary to changes within the nucleus, and specifically to changes in gene expression as modulated by telomere shortening.

Previously, we pointed out that every cell in your body is – biologically speaking – several billion years old, yet those cells only show evidence of aging during the several decades of a typical human lifespan. We each inherit a line of cells that didn’t age for billions of years, and yet begin aging during the several decades after birth. The same is true for mitochondria. Every mitochondria in the human body is at least 1.5 billion years old, the time at which the first mitochondria and eukaryotic cell joined forces. If you suggest that all aging is due to aging mitochondria, then you are immediately brought up short by the biological provenance of mitochondria. You end up forced to admit that mitochondria didn’t age for 1.5 billion years and yet (as with your cells themselves) begin aging during the decades after birth.

You inherit mitochondria that have never aged and that then age rapidly during your lifespan. If mitochondria cause aging, then why didn’t they age for the past 1.5 billion years? Why suddenly now? In short, if you want to explain aging by pointing to mitochondria, then you are going to have to back up a step and explain mitochondrial aging itself.

To put it bluntly: if mitochondrial aging causes human aging, then what causes mitochondrial aging?

As we’re just seen, you can’t very well blame “wear and tear”, since your mitochondria are all 1.5 billion years old and they did perfectly well until you came along. If mitochondria play a key role (and they do), you still have to ask why mitochondria sometimes do age and sometimes don’t, or why mitochondria didn’t age for billions of years, but then suddenly age after conception. We can’t simply ignore the question, wave our hands, and blame “free radical damage”.

Yet it is clear that mitochondria show changes during cell aging. There are two clear changes in metabolism: they become less efficient at creating energy (ATP) and they become more likely to produce free radicals (ROS). Putting it graphically, we see that as telomeres shorten, as gene expression changes, and as cells progress toward senescence, we find that the mitochondria show a decrease in ATP production and an increase in ROS production. Putting it differently, the ratio of ATP/ROS goes down with age. As our cells age, they get sloppier, taking more effort to produce usable cellular energy, while simultaneously creating more damaging ROS as they do so. To be specific, young cells typically produce about 1-4% ROS for every mole of ATP, but this percentage increases as our cells senesce. Nor, as we will see, is ROS production the only problem.

To understand why mitochondria lose efficiency, and why it is the result of telomere shortening, we need to understand a bit about mitochondria and their dependence upon the nucleus. It’s true that the mitochondria have their own 37 genes and that these code for 13 proteins that are critical to aerobic metabolism, but it is equally true that most mitochondrial enzymes are imported from the nucleus. Likewise, while the rate of mitochondrial DNA damage is 3 to 20-fold higher than that of nuclear DNA damage (due to the high concentration of mitochondrial ROS, the lack of protective histones, the lack of introns, and less effective mitochondrial DNA repair), mitochondrial DNA repair, replication, and transcription, as well as mitochondrial maintenance generally (including membrane maintenance) are entirely dependent upon the nuclear DNA. Moreover, most of the aerobic enzymes (including those required for the citric acid cycle) have components that are coded for in nuclear genes. In other words, mitochondrial function is almost entirely dependent upon gene expression in the nucleus, which is modulated by telomere shortening. The mitochondria and mitochondrial energy metabolism (including both ATP and ROS production) are completely at the mercy of nuclear gene expression, and are not independent. Aging occurs because changes in nuclear gene expression result in mitochondrial dysfunction, not the other way around.

Looking at this visually, almost all the enzymes required for normal mitochondrial function are based in the nucleus, not in the mitochondria. The mitochondria, far from being an island unto itself, is entirely dependent upon nuclear DNA, the rates of nuclear gene expression, and telomere modulation of that gene expression.

We have already pointed out that, as cells age, the mitochondria become less adept at producing energy, as well as increasingly prone to producing ROS. By implication, these two changes in energy metabolism are both the result of changes in gene expression within the nucleus, but these are far from the only changes that occur with cell aging. A young, fully functional cell has four processes which address the dangers of ROS. These four processes are:


  1. Production:           ROS are produced within the mitochondria
  2. Sequestration:     Membranes restrict ROS within the mitochondria
  3. Trapping:             Scavenger molecules “capture” ROS outside the mitochondria
  4. Repair:                 DNA repair and molecular turnover deal with ROS damage


The bulk (perhaps 93%) of ROS are produced within the mitochondria. In young cells, the rate of production is relatively low and even those ROS that are produced are generally kept within the mitochondrial membranes. As cells age (and as telomeres shorten and gene expression alters), the enzymes required for efficient energy production are turned over less rapidly, are less available, and are more likely to be denatured: the outcome is that the rate of ROS production climbs. Moreover, a similar problem is occurring within the membranes that wall off the mitochondria: the enzymes responsible for cell membrane molecules – mostly lipid molecules – are also down regulated, with the result that membrane molecular turnover slows, the percent of damaged (oxidized) lipids increases, and the membranes are increasingly porous, allowing ROS leakage to increase. Adding to the membrane problem is that membrane leakage also rises in the nuclear membranes, so the rate of DNA damage rises even as the rate of DNA repair begins to fall. In short, as telomeres shorten and gene expression changes, the mitochondria not only produce more ROS, but are more likely to leak ROS into the cytoplasm and the nucleus.

In the young cell, such ROS are rapidly trapped by multiple mechanisms, including SOD (superoxide dismutase), catalase, and other enzymes coded for in the nucleus (as well as trapping due to dietary scavenger agents, such as urate, tocopherols, etc.). As cells age, however, these scavenger enzymes are recycled more slowly and at any given time the older cell has an increasing percentage of dysfunctional ROS scavenger molecules. Worse yet, the rate of DNA repair declines, as does the rate of recycling of damaged molecules generally.

The result of these four processes is the “perfect storm”, a multiplicative set of four effects causing an exponential increase in overall cell damage.

  1. Mitochondrial ROS production increases,
  2. Mitochondrial and nuclear membrane leakage increases,
  3. ROS damage increases as scavenger efficiency declines, and
  4. Cellular responses to damage (molecular recycling and DNA repair) decline.

It is little wonder that antioxidants have little practical effect upon cell aging or age-related diseases. An increase in dietary anti-oxidants shows almost no effect upon the third of these four effects (scavenging) and no effect whatsoever upon the other three effects (production, leakage, or recycling/repair of damage.

As cells age, there are critical changes within the mitochondria as well as in the cell’s ability to respond to the increasingly dysfunctional mitochondria. However, all of these changes – in production, sequestration, scavenging, and repair – are the result of changes occurring within the nucleus. Much of what happens in cell aging can be seen in the increasing dysfunction of the mitochondria, but all of these changes are secondary to changes within the nucleus.

Specifically, it is telomere shortening and its effect upon gene expression within the nucleus that results in mitochondrial aging. Mitochondrial changes are a key part of the tragedy that plays out on the stage of cellular aging, but that tragedy is directed by the nuclear chromosomes – and by our telomeres.

Next Time: 2.8 Cell Senescence, Changes In Molecular Turnover, Extra-Cellular Molecules

1 Comment »

  1. Thanks Michael for another excellent article. Kind Regards

    Comment by Stephen Rodwell BSc — June 23, 2018 @ 8:53 am

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