Caloric restriction slows brain aging

Lou Pagnucco pagnucco at oeonline.com
Sat Jul 1 22:18:41 EST 2000


Hello Aubrey,

Thanks for the very informative reply.

I hope, though, that you are at least somewhat too pessimistic.
See my remarks below.

Cheers,
Lou Pagnucco

Aubrey de Grey wrote in message <8jl101$949$1 at pegasus.csx.cam.ac.uk>...
>
>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.

IMHO (as a layman), I tend to agree that many of these changes in gene
transcription are indeed compensatory.  However, I am inclined to think
that many are causal given that modifications of single genes have been
found which significantly increase maximum lifespan in mice, drosophila
and worms.

>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.).

Definitely.  Nevertheless, those "non-genetic" changes appear to be
down range results of genetic programs activated earlier.  Why else
would such changes be so species-specific?
The DNA arrays should allow us to spot these precursors.

>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).

Nevertheless, there are eminent gerontologists who surmise that the
increasing fraction of senescent and near-senescent fibroblasts does indeed
have deleterious effects on the extra-cellular matrix which, in turn, has
damaging effects on the cells which must rely on the ECM to maintain
their proper state of differentiation.

>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.

Amen.  This will certainly require the most powerful of supercomputers.
Such a complex multifactorial process may be too intricate for the unaided
human brain to disentangle.
>
>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).

Some compensatory changes must be beneficial.
Still, I would bet that many are detrimental.

[...]

\>Aubrey de Grey








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