Genes that ensure a long life? Not likely

The genome of a woman who was 115 years old when she died has been sequenced, and according to a report in the BBC (the analysis hasn't yet been published, but the results were reported at the recent Human Genetics meeting in Montreal), the woman was the oldest in the world at the time of her death, and had no signs of dementia, and in fact when tested for cognitive ability, was found to have the thinking facility of a woman in her 60's or 70's.

According to one of the geneticists involved, the woman had some "rare genetic changes" in her DNA.

Dr Holstege told the BBC: "We know that she's special, we know that her brain had absolutely no signs of Alzheimer's.

"There must be something in her body that is protective against dementia.

"We think that there are genes that may ensure a long life and be protective against Alzheimer's."

Ok, let's pick these few statements apart.

First, we all have "rare genetic changes" in our DNA, so in fact she should get no points for this. 

Second, is dementia really the default state for the elderly?  That is, is it right to conclude that  someone over 100 without dementia must have some innate protection against it?  A quick search suggests that the data vary wildly, and aren't strictly comparable -- a small study in Oregon found that almost 40% of the study group of people over age 97 were dementia-free, while a compilation of data from around the world, published in The Lancet in 2005 suggests that dementia comes nowhere close to being the default state in people 85 or older.  So let's say for the sake of argument that the prevalence is somewhere in between both numbers -- still, dementia is pretty clearly not the default state.

Table 1

Group mean consensus estimates (SD) for prevalence of dementia (%) for each region and age-group

	Age-group (years)
	60–64	65–69	70–74	75–79	80–84	≥85
EUROA	0·9 (0·1)	1·5 (0·2)	3·6 (0·2)	6·0 (0·2)	12·2 (0·8)	24·8 (1·0)
EUROB	0·9 (0·1)	1·3 (0·1)	3·2 (0·3)	5·8 (0·3)	12·2 (0·3)	24·7 (2·3)
EUROC	0·9 (0·1)	1·3 (0·1)	3·2 (0·2)	5·8 (0·2)	11·8 (0·5)	24·5 (1·8)
AMROA	0·8 (0·1)	1·7 (0·1)	3·3 (0·3)	6·5 (0·5)	12·8 (0·5)	30·1 (1·1)
AMROB	0·8 (0·1)	1·7 (0·1)	3·4 (0·2)	7·6 (0·4)	14·8 (0·6)	33·2 (3·5)
AMROD	0·7 (0·1)	1·5 (0·3)	2·8 (0·4)	6·2 (1·1)	11·1 (2·0)	28·1 (5·2)
EMROB	0·9 (0·3)	1·8 (0·1)	3·5 (0·3)	6·6 (0·2)	13·6 (0·8)	25·5 (2·3)
EMROD	1·2 (0·3)	1·9 (0·2)	3·9 (0·3)	6·6 (0·4)	13·9 (1·3)	23·5 (2·3)
WPROA	0·6 (0·1)	1·4 (0·1)	2·6 (0·3)	4·7 (0·6)	10·4 (1·2)	22·1 (3·5)
WPROB	0·6 (0·1)	1·8 (0·2)	3·7 (0·4)	7·0 (0·9)	14·4 (1·9)	26·2 (3·9)
SEAROB	1·0 (0·1)	1·7 (0·2)	3·4 (0·2)	5·7 (0·5)	10·8 (1·2)	17·6 (2·7)
SEAROD	0·4 (0·1)	0·9 (0·1)	1·8 (0·2)	3·7 (0·4)	7·2 (1·2)	14·4 (2·7)
AFROD	0·3 (0·1)	0·6 (0·1)	1·3 (0·2)	2·3 (0·5)	4·3 (1·0)	9·7 (1·9)
AFROE	0·5 (0·3)	1·0 (0·4)	1·9 (0·9)	3·8 (1·7)	7·0 (3·6)	14·9 (7·2)

And the fact that prevalence varies by region, being highest in developed countries, suggests either that diagnosis or record-keeping are less reliable in developing countries, or that risk increases with level of development.  If the latter is true, the idea that something innate protects against dementia -- genes, as the researcher suggests -- is less convincing.

Finally, as reported in the BBC story, "Further work [on this woman's genome] could give clues to why some people are born with genes for a long life, says a UK scientist."

Now, we noted earlier that whole genome sequences, of which there are now quite a few, have shown that we all have 'rare' variants.  At known mutation rates, we all have about 155 brand-spanking-new mutations.  Most, of course, will be in non-functional places (so far as 'function' is known).  But a few will be in known functional sites.  But the Methuselady paper suggests that she had rare longevity variants, and raised the hope that we'll find it by looking, blearily, at all 6.2 billion nucleotides in her genome.

More important by far is the flip side of this story.  With few if any exceptions, every person from whom we have whole genome DNA sequence has many variants that inactivate a gene, usually some known 'disease' variants, and large numbers of totally knocked-out (inactivated) genes...in both copies.  Yet the samples are from middle-aged or older people who don't have any particular disease.  So no one should be saying with a straight face that this lady's genome is going to reveal the Gene for Immortality.  Single variants rarely cause major traits in this sense.

Given what we already, clearly know, can there be genes "to ensure a long life"?  How would they have evolved?  Natural selection can only act on traits that affect fitness, reproductive success.  That is, traits that are apparent during reproductive years, because it's only by having more offspring than people without a given trait that a trait can become more common.  Longevity is not one of those traits. Especially decades beyond menopause.

But, ok, let's say that this woman did in fact have genes 'for a long life' -- even then it's unlikely they will be alleles that are found in significant frequency in the population.  Thus, looking for, or even finding them, in this woman's DNA will not tell us much at all that can be generalized to the rest of us.

Aging is an interesting phenomenon and there are some really important questions about it, and even some good work being done.  For example why do mice, with a largely similar genome as humans, live 2 or 3 years, while we can live over 100?   With orders of magnitude fewer cells at risk, why do mice get cancer at an age-accelerating rate that seems similar in shape to that of human cancers?  And if there is a random component in life -- and certainly at least there is the luck involved in not being affected by lethal infections, accidents, and so on -- then how do we calibrate our view of how likely is a single long-lived person is to have been so for some 'causal' reason, genetic or otherwise?

These are the scientific questions.  Instead of serious science, what this kind of warm human interest story tells us most is about the assumptions first, that everything has to be genetic, and second, even more obvious, is that everything has to be milked for its publicity and grant-justifying value.