December 9, 2013

What is aging? There are literally dozens of answers to that question, even if we restrict ourselves to purely academic views. In the days when I was the executive director of the American Aging Association, there were – or so it seemed – as many aging hypotheses as we had members of the association. Almost […]

Aging: philosophy and reality

What is aging?

There are literally dozens of answers to that question, even if we restrict ourselves to purely academic views. In the days when I was the executive director of the American Aging Association, there were – or so it seemed – as many aging hypotheses as we had members of the association. Almost all of the ideas, however, had a few problems. For one thing, each hypothesis tended to explain only a limited area of observation, such as a select body of data (just somatic cells) or a narrow part of the biological world (just mammals), rather than being in any sense universal.

Many “theories of aging” excluded tortoises, hydra, plants, nematodes, lice, seaweed, mammalian fertilization, germ cell lines, clones, or anything else of real interest. In fact, many “theories” exclude everything except human aging, and usually not all of that. Too bad: looking at the exceptional and the broadest biological sample are how you get the most scientific insight. Some species, for example, never age in the first place, which many “theories of aging” ignore completely. The second problem was that most theories were actually inconsistent with the available data, particularly when you looked at the details. Wear-and-tear theories, for example, don’t explain the immortality of the germ cell line. The most damning problem however, was that most aging “theories” simply weren’t testable: they were interesting ideas, but you could neither prove nor disprove these ideas.

In short, they weren’t theories at all.

A theory must be comprehensive, accurate, and testable. Even now, most “aging theories” are still merely observations or intuitive guesses about a narrow segment of our world. For example, some people believed that any animal had a limited number of heartbeats and that this figure somehow underlay all of aging. The fact that plants and some animals lack hearts and still age was somehow ignored, as was the observation that the facts were actually entirely inconsistent with the data. Heartbeats simply don’t predict aging.

Not that the idea made sense anyway.

Similar problems underlay most other theories, even theories that – for no logical reason whatsoever – seem to have general acceptance among the public. Endocrine (and similarly the “vital substance”) theories of aging, for example, assume that the aging clock for your entire body lies in some set of endocrine glands, but if endocrine glands time aging in the rest of your body, then what times aging in the endocrine glands? And how do we explain aging in cells? How about animals or plants that lack the candidate endocrine glands in the first place? Of course, the data shows that endocrine replacement may or may not have benefits, but has no effect whatsoever on aging. So much for endocrines. The idea was premised on correlational observations, which would be like saying that since gray hair correlates with aging, we need only dye your hair and you’ll be young again.

Well, perhaps not.

Various wear-and-tear theories are no better, even if they suit our intuitions about entropy and how our cars, houses, and cell phones “age” over time. Actually, however, living things simply don’t undergo entropy the same way at all. There are a number of idea that are central to the idea of wear-and-tear – free radicals, mitochondria, cross-linking, lipofuscin, DNA damage, waste product accumulation, and others – but none of these remain credible explanations when arrayed against the data. For example, germ cells don’t age and cell aging can be reliably reset at the time of fertilization. So much for the universal nature of wear-and-tear as an explanation for biological aging. If cells merely undergo wear-and-tear and then fall apart with time, then why don’t these cells fall apart and why can we reverse the entire process quite reliably?

There is an entire group of evolutionary theories – the disposable soma, group selection, antagonistic pleiotropy, and others – that are reasonable enough if all we want is an evolutionary explanation. These provide teleology, but don’t explain the underlying biological processes that are occurring in the organism as it ages (or doesn’t). But when we ask these theories to explain the actual pathology of aging, they point vaguely at wear-and-tear theories and shrug. Good evolutionary science perhaps, but they miss the point. We would like to know exactly what does happen as we age, not why it should happen.

While these notions fail to explain the available data – including the fact that fertilization resets cell aging, for example – the more daunting issue is that most of these explanations are not theories at all, but merely loosely-stated hypotheses.

The critical element to ANY scientific theory is that is must be disprovable.

I could tell you that “invisible and unknowable forces cause aging”, but if they are invisible and unknowable, then they can’t be proven or disproven. This is a faith, not science and certainly not an explanation of aging. I have every respect for faith, but faith isn’t science and faith doesn’t help me provide clinical therapy or offer a viable explanation for how to improve medical care when you get sick.

A good theory makes a testable hypothesis.

At the moment, there is only one theory of aging that meets our three criteria of being comprehensive, consistent with the known data, and testable. That theory – the so-called telomere theory of aging – is, unfortunately, rarely spelled out in detail and almost universally misunderstood in the first place. For example, many people assume that this theory suggests that aging is determined by telomere length, while in reality it suggests that aging is determined by a changes in telomere length.

The telomere theory of aging has so far been tested in cells and tissues and in both cases the results were consistent with the theory: when you reset telomere lengths, you reset aging, whether in humans or in animals, in cells or in tissues. The theory has also been tried in vivo, using an oral compound, and the initial results likewise support the theory. These various experiments underline the importance practical interventions over simplistic explanations: if you can’t change it, you can’t prove it. Science demands that a theory be testable; the medical viewpoint demands that a theory offer a potential intervention. If you can’t test it, then it isn’t science; if you can’t intervene, then it isn’t medicine.

Our intent is to test a theory, but far more importantly – to us and to everyone else – our intent is to offer interventions.

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