The Lens, Progerias and Polycausality

by johnswentworth3 min read8th Mar 20206 comments

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AgingGears-LevelWorld Modeling
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Fun fact: the lens of a human eye consists mostly of fiber deposits which are never broken down - they do not turn over. Furthermore, new fiber layers are constantly added throughout life, so the lens thickens linearly by about 25 microns per year. Starting at around 3.5mm in infancy, it reaches 5.5mm in old age.

The main clinical result of this is the practically-universal need for glasses for close-up vision in people over 55 years old.

(Source: Physiological Basis of Aging and Geriatrics; the section on the eye is one of the most detailed in the book.)

Besides being a simple, self-contained gear in its own right, the growth of the lens is a clear, knock-down example of an independent root cause of one symptom of aging. We know exactly what’s accumulating in a nonequilibrium fashion: the fibers of the lens. It’s wildly unlikely that the growth of the lens is a root cause for other symptoms of aging - like wrinkles, atherosclerosis, Alzheimer’s, cancer, muscle degeneration, etc. So, we have a clear case for polycausality - at least for one symptom of aging.

That said, there’s a fair bit of evidence that most symptoms of aging share a common root cause, or at least a common intermediate. Qualitatively, many/most symptoms of aging in a wide variety of tissues:

  • Look similar at the cellular level - there’s a loss of homeostasis, with cells dying off faster than they’re replaced, high levels of misfolded protein aggregates (a.k.a. junk), and markers of chronic inflammation
  • Follow a similar population-level onset/progression timetable: no noticeable problems from youth through mid-twenties, gradual onset/progression throughout middle age, then rapidly accelerating breakdown around 50-60 years of age and older. Some examples: cancer incidence, muscle loss, atherosclerosis. Google a performance metric which declines with age, and you’ll probably see the pattern.
  • Are correlated - someone who has one problem early is likely to have others early, and vice versa. See the literature on physiological/biological aging clocks for details.

The growth of the lens does not follow this pattern - it’s just a straight-line linear growth starting from childhood, without any unusual role of chronic inflammation or misfolded proteins or other typical aging-associated characteristics. On the other hand, there are other contributing factors to old-age vision problems which do follow the usual pattern - for instance, the loss of pupil muscle mass.

Besides the growth of the lens, there are a handful of other possible root/intermediate causes of aging symptoms which don’t follow the usual pattern. None of them are as conclusive an example as the lens, but they may be involved in nastier diseases. In particular: the thymus is an organ which trains adaptive immune cells to distinguish pathogens from healthy host cells. That organ begins to shrink (called “thymic involution”) even in the first year of life, and steadily loses most of its mass by old age. I’ll likely have a full post on that later.

Progerias

One interesting source of evidence about common root causes of aging symptoms is accelerated aging diseases, a.k.a. progerias. I’ll talk about two: Werner Syndrome (WS) and Hutchinson-Gilford Progeria Syndrome (HGPS).

Werner syndrome is the progeria which most closely resembles true aging. People with WS develop normally through puberty, but then develop a laundry list of aging symptoms early:

  • Gray hair
  • Hair loss
  • Wrinkles
  • Skin hardening/tightening
  • Loss of fat tissue
  • Atrophy of gonads
  • Cataracts
  • Atherosclerosis
  • Type 2 diabetes
  • Muscle degeneration
  • Bone loss
  • Cancer

(you can find all this on the wikipedia page). Perhaps even more notable: changes in gene transcription associated with WS closely resemble the transcription changes associated with aging.

What causes this remarkably aging-like disease? Mutation of a gene called WRN (short for Werner), which is involved in repair of several types of DNA damage. The damage does still get repaired (otherwise people with WS wouldn’t be alive at all), but it’s slower, so presumably there’s a higher steady-state level of DNA damage. This is consistent with other lines of evidence which I may talk about in future posts: high levels of DNA damage are associated with aging.

The other type of progeria we’ll discuss is HGPS. HGPS also shows many aging-like symptoms:

  • Hair loss
  • Wrinkles
  • Skin hardening/tightening
  • Atherosclerosis
  • Muscle degeneration
  • Bone loss

But even more notable is the symptoms of aging which are not associated with HGPS, specifically:

  • Cancer
  • Arthritis

(Note: I didn’t comprehensively check every symptom of WS against HGPS, so don’t read too much into the differences between the two lists above.)

What would cause so many aging-like symptoms, but not cancer? HGPS is caused by mutation of a nuclear envelope protein; without it, the cell nucleus has a weird shape (striking picture here). The main result is that cells have trouble dividing - the folded-up nuclear envelope gets in the way of chromosome arrangement when the nucleus is supposed to divide. The mutation limits cell division, which we’d expect to lower homeostatic counts of a broad variety of cell types.

Assuming that’s the main mechanism, we’d expect HGPS to show the symptoms of aging associated with cell loss - e.g. hair loss, muscle degeneration - but not the symptoms associated with biological stressors like DNA damage - e.g. cancer and inflammatory diseases like arthritis. For some symptoms which aren’t yet fully understood - e.g. wrinkles or atherosclerosis - HGPS is a hint that cell loss is probably a key mediating factor.

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