Accumulated damage to mitochondrial DNA is an important component of aging. Mitochondria are the cell's powerplants, and their DNA, separate from that contained in the cell nucleus, is vulnerable to the reactive by-products of mitochondrial operation. Intricate DNA repair processes exist, but eventually they become outmatched, and broken mitochondria dominate in a small but significant fraction of our cells. These cells become very active exporters of harmful, reactive biochemicals, which in turn causes progressively greater damage to biological processes throughout the body - and in the fullness of time this helps to kill you.

What we would like to see happen in the near future is for any one of the several lines of research into mitochondrial repair to advance to completion. Whole body repair of mitochondrial DNA damage conducted once every two or three decades would eradicate this important contribution to degenerative aging.

In the meanwhile, here's an open access paper that looks more closely at mitochondrial damage over time in the eyes, a process that contributes to the formation of catacts:

Oxidative damage resulting from reactive oxygen species (ROS) is considered to be a major risk factor in the pathogenesis of both age-related and diabetic cataract. ROS is mostly generated within the mitochondria in lens epithelium and the superficial fiber cells, which are highly reactive and can damage macromolecules in living cells, [causing] mutagenesis and cell death. Mitochondrial DNA (mtDNA) is highly susceptible to the damage produced by ROS because of its close proximity to ROS generation through the respiratory chain.

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The 'mitochondrial theory of aging' suggests that aging results from declining mitochondrial function, due to high loads of damage and mutation in mtDNA. Oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases, in cancer, and in aging . Under normal growth conditions, ROS leads to a low level of mtDNA and nuclear DNA (nDNA) damage, which is rapidly repaired, and most oxidative DNA lesions are repaired by the base excision repair (BER) pathway

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The purpose of the study presented here was to determine if there is an increased mtDNA [damage] in the lens with age.

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The gene expression [of] key BER enzymes decreased with age, which caused a decrease in the repairing capability of the mtDNA and the accumulation of mtDNA damage. The increased mtDNA damage and decreased expression of BER enzymes may cause a "vicious cycle" of oxidative stress that contributes to the accumulation of mtDNA mutations and age-related cataract pathogenesis.

As hinted at here, the growth of mitochondrial damage, like most aspects of biology, is a very dynamic process. Human biology strives to maintain itself, and most of its self-repair systems are very effective indeed - in the young, at least. Aging is as much a progressive failure of biological repair mechanisms as it is an accumulation of damaged and misplaced machinery.

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Science is as much about investigating what we do not see as it is about investigating what we do see. For example, from a recent open access paper:

Small rodents in captivity routinely reach ten times their mean life span in the wild. Why is it then that in human populations with an average life span of 40 to 80 years nobody has ever lived to 400 years old or more?

This is a fine and valid question. Why do we see little variation in human life span in comparison to that of smaller and more short-lived mammals?

The authors of this paper performed an analysis of mortality statistics across different species of mammal, the results of which lead into a very interesting and readable discussion on the interaction between evolutionary pressures and age-related frailty. This is all part of the larger question of why we age, and why we age in the way we do.

In particular, these researchers argue that the end stages of frailty in aging - senescence - do not result from a lack of evolutionary pressure later in life. But the fact that senescence still exists despite pressure for increased evolutionary fitness is telling us something important about the nature of mammalian biochemistry. From the paper:

A clear implication of our study, therefore, is that long-lived mammals are more likely than short-lived mammals to reach an age when their lives are affected by senescence (that is, an age closer to their maximum life span). In other words, our analysis suggests that senescence occurs at a much younger age, relative to the mean natural life span, in longer lived mammal species.

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An age when senescence retards survival (i.e. near to the maximum life span) is reached by a higher proportion of individuals, and therefore remains under increasingly high selection pressure, in natural populations of longer lived mammal species ... This implies a minimum rate of senescence has been unavoidable in the evolution of mammals and could place a limit on their maximum life span, preventing humans from [naturally] reaching Methuselah-like ages. Because senescence affects survival in long-lived species despite relatively strong opposing selection pressure, they have probably evolved mechanisms to delay its negative effects. Retarding senescence further seems to be unavailable to natural selection.

This sort of theorizing is a sideline to the real work of extending healthy human longevity. We don't need to know how aging came to exist in its present form in order to be able to repair the biochemical damage that causes aging and thus reverse its effects. But it is nonetheless very interesting.

Turbill, C., & Ruf, T. (2010). Senescence Is More Important in the Natural Lives of Long- Than Short-Lived Mammals PLoS ONE, 5 (8) DOI: 10.1371/journal.pone.0012019

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A great deal of medical research into aging is built upon a foundation of correlation studies: what can we identify as more often occurring for patients who suffer from a particular age-related condition? Are there environmental factors, lifestyle choices, or genetic differences that are statistically linked to the occurrence of this condition? The next step that follows from the identification of such correlations is to pick them apart looking for commonalities. Why do these many correlations exist, and do they exist because of one underlying mechanism?

For example, see this open access paper that proposes chronic inflammation as the causative process for a range of correlations:

Tobacco smoking, physical inactivity and resulting obesity are established risk factors for many chronic diseases. Yet, the aetiology of age-related diseases is complex and varies between individuals. This often makes it difficult to identify causal risk factors, especially if their relative effects are weak. For example, the associations of both obesity and air pollution with several age-related diseases remain poorly understood with regard to causality and biological mechanisms. Exposure to both, excess body fat and particulate matter, is accompanied by systemic low-grade inflammation as well as alterations in insulin/insulin-like growth factor signalling and cell cycle control.

These mechanisms have also been associated in animal and some human studies with longevity and ageing in more general terms. In this paper, it is therefore hypothesised that they may, at least in part, be responsible for the adverse health effects of obesity and air pollution.

Inflammation is very much a bugbear, and in recent years a great deal of research has focused on just how chronic inflammation and the failing immune system contributes to degenerative aging. Researchers are also making good progress on understanding exactly how excess fat tissue produces chronic inflammation and damages the immune system in the process.

Nicole M. Probst-Hensch (2010). Chronic age-related diseases share risk factors:
do they share pathophysiological mechanisms and why does that matter? Swiss Medical Weekly DOI: 10.4414/smw.2010.13072

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Metformin is one of the known calorie restriction mimetics amongst drugs presently in use by the medical establishment. A calorie restriction mimetic is a drug that can reproduce some of the beneficial changes to metabolism exhibited during the practice of calorie restriction, which hopefully in turn leads to improved health and extended healthy life span.

Metformin has been shown to modestly increase maximum life span in mice, though by much less than is possible through calorie restriction:

chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice.

In human medicine, metformin is primarily used as an anti-diabetic treatment, which has led to speculation as to just how much of the calorie restriction effect on health and longevity is due to changes in insulin metabolism - such changes made directly in genetically engineered laboratory animals have been shown to significantly affect longevity as well.

Here, however, I will point you towards a paper that shows much of the effect of metformin to reside in the mitochondria, the cell's power plants. Regular readers will by now know that our mitochondria are very important determinants of aging and longevity, and the accumulated damage suffered by mitochondria - caused by the reactive oxygen species they produce as a consequence of their operation - produces some fraction of the aging process. These reactive oxygen species include hydrogen peroxide, H2O2, and, as it turns out, metformin reduces the rate at which H2O2 is produced by mitochondria without otherwise impairing their operation:

In conjunction with improved glycemic control, metformin treatment reduced H(2)O(2) emission in muscle from obese rats to rates near or below those observed in lean rats ... Surprisingly, metformin treatment did not affect basal or maximal rates of O(2) consumption in muscle from obese or lean rats. ... These findings suggest that therapeutic concentrations of metformin normalize mitochondrial H(2)O(2) emission by blocking reverse electron flow without affecting forward electron flow or respiratory O(2) flux in skeletal muscle.

Since I'm not greatly in favor of efforts that only slow aging, I see this sort of research as more in the way of a confirmation of the importance of mitochondrial damage - and the need to put more resources towards mitochondrial repair with the aim of reversing the effects of aging.

Kane DA, Anderson EJ, Price JW 3rd, Woodlief TL, Lin CT, Bikman BT, Cortright RN, & Neufer PD (2010). Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats. Free radical biology & medicine, 49 (6), 1082-7 PMID: 20600832

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The future of our organs is as much artificial as it is fleshy. In the competition to develop a source of replacement organs built from scratch, the biotechnology-focused materials science researchers will give the tissue engineers a run for their money. Viable artificial hearts are in trials at the present time, for example, at the same time as decellularization of donor heart values is employed to build replacement parts for injured hearts. Neither path ahead is quite ready for prime time, but a wide range of trials are underway for early stage products, and an even wider range of work is taking place in the laboratory.

So to the future of bioartificial organs. A computer doesn't look much like a brain, a slide-rule, or a typewriter. The bioartificial pancreas of the future won't look a whole lot like the pancreas you're carrying around with you at the moment. In parallel to work on regenerative medicine and repair of aging - aiming to maintain the body we have - we will see a great breadth of development in semi-organic prostheses and other functional replacements, and the growth of support infrastructure for that technology.

At the end of the day, some decades from now, it'll all be nanotechnology of course: fully artificial all the way down to the carefully tuned cell-substitute nanomachines. But in the meanwhile, and in the early days of this biotechnology revolution, competition is good for progress. On this subject, I see that matters are moving ahead for the kidney:

UCSF researchers today unveiled a prototype model of the first implantable artificial kidney, in a development that one day could eliminate the need for dialysis. The device, which would include thousands of microscopic filters as well as a bioreactor to mimic the metabolic and water-balancing roles of a real kidney, is being developed in a collaborative effort by engineers, biologists and physicians nationwide. ... [The] goal is to apply silicon fabrication technology, along with specially engineered compartments for live kidney cells, to shrink that large-scale technology into a device the size of a coffee cup. The device would then be implanted in the body without the need for immune suppressant medications, allowing the patient to live a more normal life.

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The two-stage system uses a hemofilter to remove toxins from the blood, while applying recent advances in tissue engineering to grow renal tubule cells to provide other biological functions of a healthy kidney. The process relies on the body's blood pressure to perform filtration without needing pumps or an electrical power supply.

Cast your mind back and recall what a mobile phone looked like in 1980, 30 years ago now. Consider, in turn, what a bioartificial kidney, pancreas, or liver will look like in 2040, 30 years from now. The same forces of progress are at work.

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