Many of the interventions demonstrated to produce interesting effects on the pace or state of aging are challenging to learn from. This is the case because these interventions change so much of the operation of metabolism as to make it hard to pick apart what is most relevant to the progression of aging versus what is a side-effect.
Calorie restriction is the canonical example – it alters the entire laundry list of cellular processes thought relevant to aging, and a good many others besides. Similar issues arise when looking at heterochronic parabiosis, as linking the circulatory systems of a young animal and an old animal changes the signaling environment profoundly.
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This makes it all too easy to pull together an argument for a specific area of metabolism to be important in aging. In the case of iron metabolism, the subject of today's open access paper, there is a reasonable case to be made. The challenge, as is the case for just about every other argument for process A or process B to be important in aging,is how does one prove the hypothesis? That iron metabolism is altered in calorie restriction is only mild support at best, for the reasons given above.
Proof of relevance in aging requires targeted interventions that address only the one specific causative mechanism. On the rejuvenation, damage repair side of the house, senolytic drugs to destroy senescent cells are a recent example. Animal studies using senolytics have proven that the accumulation of senescent cells causes a sizable fraction of age-related pathology. But one might also look at the compensatory therapy of antihypertensive medication, and see it as a way to prove that raised blood pressure is an important intermediary mechanism in aging, caused by underlying molecular damage, and capable of itself causing a meaningful amount of downstream structural damage. In the case of iron metabolism, I'm not sure that any of the example interventions given in today's paper rise to the level of being sufficiently narrow and targeted to prove the point.
Iron: an underrated factor in aging
All life forms require the element iron as a constituent of their biochemical systems, iron being used in producing ATP in mitochondria, in cytochromes and hemoglobin, and in many other uses. Iron is essential for organismal growth and maintenance, so all life, from bacteria and algae to mammals, have developed the means to collect and store iron from their environments; this centrality of iron for all life suggests that iron may be involved in aging. Most organisms, including humans, have no systematic means of ridding themselves of excess iron. Whether this lack of ways to dispose of excess iron came about due to a relative scarcity of iron, or because the detrimental results from excess iron were relatively rare in an environment in which few organisms died from natural aging, is a question that remains to be answered. Whatever the answer to that may be, most organisms accumulate iron as they age.
A problem that organisms face in the use of iron in biological systems is protecting cells from iron damage. The very property of iron that makes it useful, its ability to accept or donate electrons, also gives it the ability to damage molecules and organelles via the Fenton reaction, in which iron reacts with hydrogen peroxide, leading to the formation of the highly reactive and toxic free radical, hydroxyl.
Most iron in cells is bound to proteins and other molecules that safely store it and prevent it from interacting with other macromolecules. In mammals, ferritin and transferrin are such proteins; hemoglobin is, however, the quantitatively most important iron depot in mammals. In theory, these storage proteins should be enough to protect organelles and macromolecules from iron's reactivity, but in practice another process becomes perhaps more important, and that is iron dysregulation. Storage proteins such as ferritin can themselves be damaged, leading to “leakage” of free iron, which can then react with and damage cellular structures, which in turn can lead to organ damage and the deterioration associated with aging. Whether this damage associated with aging is in fact a cause or consequence of aging of course remains to be determined, but as we shall see, there are several other reasons to think that iron is a driver of aging.
Source: Fight Aging!