Re : Cornering the causes of aging (was Re: AGING: Accumulation of DNAdamage)

From: Joao Pedro de Magalhaes (
Date: Sat Jul 01 2000 - 06:21:09 MDT


>>Werner's syndrome is caused by one single gene. This alone rules out the
>>possibility that all age-related pathologies cannot have an upstream
>>regulator. In addition, it also provides strong evidence that other simple
>>(probably not with just one gene but a few more) mechanisms can be upstream
>>of most, if not all, aging pathologies.
>Trouble with this suggestion (which I hope is correct!) is that we don't
>know of any individual humans--the species best able to take care of itself
>via foresight, etc--who have escaped fatality with lucky mutations. Or are
>they in hiding (as in Poul Anderson's novel THE BOAT OF A MILLION YEARS)?
>Or haven't there been enough humans around at any one time until lately for
>them to emerge and then survive in the midst of plagues, wars, starvation,
>etc? Are the mutational immortals all under 10 years of age, most of them
>in China and India?

Good question. Well, obviously senescence is caused by more than one gene;
which means non-senescent mutants would be very unlikely to appear
overnight. Even so, as to why we never witness non-senescing mammals can
have a couple of explanations: (1) perhaps Williams was right and
antagonistic pleiotropy is behind aging: this means that the genes causing
senescence are essential at earlier development or they are essential, for
example, for certain advanced brain functions (one old proposal is that
animals such as birds and mammals have senescence due to being warm-blooded,
making them more intelligent but also leading to larger amounts of damage);
(2) my favorite explanation is that the mutations needed to dispose of
senescence are probably (at least to some extent) gain-of-function mutations
(as opposed to Werner's syndrome). Here's a practical example: DNA damage
causes senescence (Robert will love me saying this, but it's just an
example, I'm not endorssing the DNA damage theory!) and Werner's syndrome is
caused by defects in DNA repair. To eradicate senescence you need to make
DNA repair enzimes more efficient (up to the level of non-aging species).
Obviously such developments by random mutations are extremely rare (perhaps
you need to create a whole new enzime, one that was lost when mammals
evolved from reptilians); however, human DNA repair enzimes are a little bit
more efficient than chimpazees, giving us our increased longevity (I'm being
over-simplistic here, the differences between us and chimpazees might be
related to an improved resistence to age-related pathologies and not a
decreased rate of senescence; but you can think of mice vs. humans and
follow the same reasoning). Interestly, and continuing my speculatory
example, using transgenics by inserting DNA repair enzimes of reptilians in
humans you can easily, and without having to radically change the genome,
achieve this.

Best wishes.

Joao Pedro de Magalhaes
The University of Namur (FUNDP)
Unit of Cellular Biochemistry & Biology
Rue de Bruxelles, 61
B-5000 Namur BELGIUM

Fax: + 32 81 724135
Phone: + 32 81 724133
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