Reviewing the Mitochondrial Basis of Aging

Here I'll point out a recent and very readable open access review on the topic of mitochondrial contributions to the aging process. If you'd like a high level tour of present mainstream research community thinking on the numerous mechanisms that link or may link mitochondria to aging, this is a good place to start. Where it falls down, as is often the case, is in the process of moving from the data, that mitochondria contribute to aging, to what to do about the data, meaning strategies for the development of therapies to address mitochondrial dysfunction. When considering that goal, most present research groups immediately reach for pharmaceutical development with an eye to altering mitochondrial activities, such as by artificially recreating some of the calorie restriction response known to both reduce mitochondrial dysfunction and slow aging. The anticipated outcomes are not ambitious - a modest slowing in the progression of dysfunction at best - while the costs and uncertainties of pharmaceutical development to manipulate aspects of cellular metabolism remain as great as ever.

Mitochondria swarm in their hundreds inside each of our cells. They are the remnants of symbiotic bacteria from the earliest era of evolution, over time losing all but a fraction of their original genome. That remnant mitochondrial DNA (mtDNA) passes from mother to offspring, and there are a comparatively small number of varieties across the entire human population, each springing from a single ancestral mutation. Mitochondria multiply like bacteria, and are culled when damaged by quality control mechanisms inside the cell. They also merge, promiscuously swap protein assemblies and DNA, and can even transfer between cells, all of which makes understanding their behavior and the consequences of that behavior quite the challenge. Mitochondria play numerous crucial roles in the cell: they generate fuel for cellular processes in the form of adenosine triphosphate (ATP), and steer forms of programmed cell death such as apoptosis, for example.

In the SENS view of mitochondria in aging, it is the mitochondrial DNA that is critical. This DNA is both less stringently maintained than is our nuclear DNA and more vulnerable to damage. It sits right next to the highly energetic process of ATP production inside each mitochondrion, a process that produces reactive, potentially damaging molecules as a side-effect. Some rare forms of damage to mitochondrial DNA can deny necessary protein machinery to the mitochondrion, and as a result spawn dysfunctional mitochondria that are unfortunately also resilient to removal by quality control mechanisms. The damage multiples every time such a mitochondrion divides and replicates its broken DNA. These damaged mitochondria can quickly take over their cell, turning it into a source of damaging, reactive molecules that can spread throughout tissues and the bloodstream. The count of these cells grows with age: it is all a numbers game, a rare event that happens often enough to create a small class of cells that contribute significantly to age-related disease and dysfunction.

The complete fix for this particular contribution to the aging process, rather than just slowing it down, is to find some way to reliably and globally deliver the missing proteins that are encoded by broken mitochondrial genes. The possible approaches include: gene therapy to deliver new mitochondrial DNA or destroy the broken DNA; delivery of entire fresh mitochondria so that cells can adopt them; direct treatment with the necessary proteins, wrapped in delivery mechanisms that can get them to the mitochondria where they are needed; or the present SENS methodology of allotopic expression in which gene therapy is used to deliver suitably edited versions of mitochondrial genes into the cell nucleus, creating a permanent backup supply of the necessary protein machinery. These are all works in progress, but allotopic expression of single mitochondrial genes to treat inherited mitochondrial disease has, with the help of SENS Research Foundation funding some years ago, now reached the stage of serious biotech industry development. None of this is mentioned in the review paper below, and this is typical of much of the research community, sadly.

The Mitochondrial Basis of Aging

While, from an evolutionary viewpoint, the notion of antagonistic pleiotropy has been exclusively applied to our genetic inheritance, it actually provides a useful framework to understand the role of mitochondria in aging. Perhaps, no structure is so intimately and simultaneously connected to both the energy of youth and the decline of the old. The revelation of these complex and antagonistic functions of mitochondria has slowly transformed how we view this subcellular organelle. Mitochondria can no longer be viewed as simple bioenergetics factories but rather as platforms for intracellular signaling, regulators of innate immunity, and modulators of stem cell activity. In turn, each of these properties provides clues as to how mitochondria might regulate aging and age-related diseases.

It has been long appreciated that aging in model organisms is accompanied by a decline in mitochondrial function and that this decline might, in turn, contribute to the observed age-dependent decline in organ function. Similarly, a decline in mitochondrial function in humans has also been observed; again, this decrement may predispose humans to certain age-related diseases. It is also known that mitochondrial mutations increase in frequency with age in both animal models and in humans, although the levels and kind of mutations appear to differ between tissues and even within tissues. While some have speculated that the increased levels of mitochondrial mutations contribute to aging and age-related diseases, others have questioned whether these mutations ever reach a significant enough level to contribute to the aging process.

Mitochondria as Regulators of Stem Cell Function

While aging is accompanied by a general decline in mitochondrial function in all tissues, the effects of mitochondrial dysfunction might be particularly important within certain specialized cell types. Since a decline in adult stem cell function is thought to contribute to various aspects of aging, the role of mitochondrial dysfunction in stem cell biology has become a subject of increasing interest. One clear connection between mitochondria and stem cell function has come from the analysis of mtDNA mutator mice. Several reports have analyzed the stem cell function of these mice and found a range of defects. It should also be noted, that the level of mitochondrial mutation seen in these models is also dramatically higher than that seen during the normal aging process, which may account for why the observed stem cell defects do not faithfully recapitulate what is seen during normal aging.

Mitochondria and Cellular Senescence

There is a strong link between mitochondrial metabolism, reactive oxygen species (ROS) generation, and the senescent state. Almost four decades ago, it was noted that the lifespan of human cells in culture could be significantly extended by culturing the cells in a low-oxygen environment. Similar relationships have been observed between other regulators of senescence and ROS, including the p53 target and cell-cycle regulator p21, which also appears to regulate senescence in a redox-dependent fashion. All of these observations fit well with the long-standing notions of the free-radical theory of aging that postulated a causal role for ROS in the aging process. Nonetheless, there are a number of observations that suggest that the cellular effects of ROS, with regard to inducing senescence, do not unequivocally transfer to organismal aging.

The Mitochondrial Unfolded Protein Response and Longevity

The mitochondrial unfolded protein response (UPRmt) is a stress response pathway initially characterized in mammalian cells in which there was either a depletion of the mitochondrial genome or accumulation of misfolded proteins within the mitochondria. In either case, it was noted that this mitochondrial perturbation triggered a nuclear transcriptional response that included the increased expression of mitochondrial chaperone proteins. While initially described in mammalian cells, the biochemistry and genetics of this pathway have been predominantly studied in C. elegans. It is now clear that the UPRmt regulates a large set of genes that not only involve protein folding but also involve changes in ROS defenses, metabolism, regulation of iron sulfur cluster assembly, and, modulation of the innate immune response. In general terms, all of these changes allow for a restoration of mitochondrial function while, at the same time, re-wiring the cell to temporarily survive as best as possible without the benefit of full mitochondrial capacity.

Mitophagy in Aging

If misfolded proteins stemming from mtDNA mutations or proteotoxic stress accumulate to a level that exceeds the capacity of the UPRmt, autophagy of mitochondria (mitophagy), or piecemeal autophagy of mitochondrial subdomains, appears to mitigate mitochondrial impairment. Consistent with the suggestion that mitophagy protects animals from loss of mitochondrial function during aging, mitophagy rates decrease in the dentate gyrus with age and upon human huntingtin overexpression.

Mitochondria and Inflammation

One of the hallmarks of aging is the development of a low-grade, chronic, sterile inflammatory state often deemed "inflammaging". The development of this state, characterized in part by increased circulating inflammatory biomarkers such as interleukin (IL)-6 and C-reactive protein, is a known risk factor for increased morbidity and mortality in the elderly. Increasingly, there is a connection between mitochondrial function and the activation of this enhanced age-dependent immune response. Mechanistically, this connection can, perhaps, be traced back to the bacterial origins of the present-day mitochondria. As opposed to nuclear DNA, mtDNA (like bacterial DNA) is not methylated. The immune system has adapted to this subtle difference and has evolved strategies to recognize non-methylated DNA, primarily through members of the Toll-like receptors, including TLR9. Presumably, this response allows rapid activation of the immune system in the setting of bacterial infection. Besides releasing non-methylated DNA, damaged mitochondria, like bacteria, can release formyl peptides that can signal through the formyl peptide receptor-1 to trigger an immune response. Both mtDNA and mitochondrial formylated peptide can be viewed as mitochondrial-derived damage-associated molecular patterns (DAMPs) that are known to stimulate the innate immune system.


Taken together, these observations suggest that mitochondria can be intimately linked to a wide range of processes associated with aging, including senescence and inflammation, as well as the more generalized age-dependent decline in tissue and organ function. In many of the early studies, the association between mitochondria and the aging process was mostly correlative. Increasingly, however, causative connections are being established. This suggests that attempts to rejuvenate mitochondrial function or improve mitochondrial quality control might be an effective strategy to combat aging. Toward this goal, there are a number of ongoing efforts to develop small molecules to therapeutically augment mitochondrial biogenesis. Similarly, raising NAD+ levels in older mice appears to restore mitochondrial function. As such, there is considerable enthusiasm to develop methods to increase NAD+ levels, either through direct supplementation or by altering NAD+ metabolism. Pharmacologic activation of mitophagy is another approach that might be widely beneficial in patients with age-related neurodegenerative disorders or to combat aspects of normal aging. As such, the next decade appears to hold considerable promise for developing a wide range of effective mitochondria-targeted therapies. With such agents, clinical trials can ultimately test the very tenable hypothesis that reversing the decline in mitochondrial function will slow, or even reverse, the rate at which we age.