Caloric restriction slows brain aging

Tom Matthews tomatth at
Sun Jul 2 19:46:50 EST 2000

Aubrey de Grey wrote:
> Lou Pagnucco wrote:
> > Below is a summary of a paper just published in Nature Genetics which
> > demonstrates that genes (at least in lab mice) that are upregulated
> > during aging in the brain (associated with inflammation and the stress
> > response) are repressed by caloric restriction.  Presumably, CR should
> > retard brain senescence.
> >
> > It is interesting that gene chips were central to this analysis.  The
> > secrets of the aging process are finally being unraveled.
> While I agree with the widespread sentiment that microarray and other
> genomic analysis techniques can tell us a great deal about cell biology
> in general and aging in particular, I think it may be worth pointing out
> the limitations of such work.  I participated last weekend in a small
> meeting ostensibly focused on reversing human aging; Weindruch also took
> part and several other participants were also genomics afficionadios.
> I found it necessary to spell out rather forcefully that what we get by
> microarray and related experiments is a picture of the **coordinated**
> gene-expression changes which occur during aging, and that such changes
> are almost entirely descriptive of what cells are doing to *compensate*
> for the primary, accumulated losses of function that define the process
> of aging and its rate.  Those primary processes themselves, by contrast,
> are either non-genetic (such as accumulation of protein cross-links or
> of lipofuscin), or non-coordinated (such as nuclear or mitochondrial
> mutations, which affect different genes (if any) in each cell), or both
> (such as cell loss in glands, muscle, heart, some brain areas, etc.).
> Even changes that one might guess are moderately uniform within a given
> tissue, such as telomere shortening, are now known not to be (such that
> one in 10,000 or so dermal fibroblasts shows senescent gene expression
> in old age but the rest don't, for example).  Moreover, microarray data
> give virtually no clue as to the relative importance of these various
> primary processes, because the changes they reveal are compensations for
> the cumulative effect of all the primary processes mixed together.
> This has very profound implications for the utility of microarray data
> in anti-aging research.  For example, an intervention which restored
> the expression levels of many (or all) genes in an elderly individual
> to youthful levels in an elderly individual would be predicted to be
> *harmful*, because it would be stopping the body from making the best
> of a bad job (i.e. reacting, by gene-expression tuning, to the primary
> changes listed above).

This is the same (logically sound) argument used by those who suggest
that hormone replacement may be life shortening while at the same time
increasing the quality of life in the earlier aged years.

> The value of such analyses may in reality be
> restricted to the (important, but limited) field of biomarkers of
> "biological age".  The Nature Genetics study, for example, identifies
> "selective" attenuation by CR of gene expression changes which occur
> during aging, thereby providing evidence that those genes whose change
> in expression was not attenuated are less good markers of biological
> age than the ones which did change.  Another application which follows
> from this is that a candidate CR mimetic (a chemical proposed to trick
> the body into thinking it's on CR when it isn't, and thence -- with luck
> -- extending one's lifespan) could be evaluated for its likely efficacy
> by determining how similar its effects on gene expression are to those
> seen in CR.

This is very similar, but of shorter duration, to the manner in which
CR'ed animals are nowadays used as a second set of "controls" during
studies of other antiaging interventions (such as a particular nutrient
or mix of nutrients).

> A wider applicability to anti-aging research -- especially
> reversal of aging -- is, by contrast, very hard to see.

Even though I am an extreme optimist with respect to conquering aging
and supremely desirous of an unbounded life-length, I want to say how
delighted that I am to read Aubrey's cogent and lucid interpretation of
the value, and lack thereof, for the new microassay technique. I have
subconsciously "known" this to be true since I first read about this
technique and had said so to many people, but I had never got down to
attempting to construct a fully worked out explanation for that
"feeling". Aubrey has now saved me the trouble and, of course, stated it
much better than I possibly could with my current level of knowledge.

> It is therefore
> regrettable that many of those involved in such work are allowing this
> distinction to become blurred in the public mind -- and, I increasingly
> find, in their own.

I very much agree, but I think that "regrettable" is inappropriately
Both too much optimistic, unrealistic hype, and too much pessimism are
counterproductive to real progress toward any goal. But when the goal is
so momentous as human lifespan extension such errors of judgment are
potentially fatal to many people and almost certainly fatal to some.

Tom Matthews

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