Paris IPSEN Conference

Samuel Cronin samuelc at MAX.ROEHAMPTON.AC.UK
Tue Apr 23 07:27:59 EST 1996

Dear all, 

Last friday April 19 I attended a one-day symposium in Paris
titled 'Longevity: To The Limits and Beyond' which was hosted by
Foundation IPSEN. The timing and setting of the Paris conference
was particularly appropriate following the recent recognition of
Mme Calment's claim to be over 120 this year. Since many of the
topics discussed during this meeting would be of interest to the
members of this list I have written a summary of the exchanges
which took place.

The general theme of all the discussions were based on the
current global trends towards decreasing mortality and higher
life expectancy, and to try to answer the question as to whether
or not there is a limit to human life expectancy and if so what
is it? It was well attended by 100-150 researchers with speakers
representing both demographers as well as biologists including,
among others, Jay Olshansky, Jim Vaupel, Jacques Vallin, Tom
Kirkwood, Francois Schachter, Raj Sohal, Tom Johnson and Caleb
'Tuck' Finch.

First up was Jay Olshansky who put forward his argument that, as
previously found in the US, in France there appeared a practical
(as oposed to biological) limit to life expectancy. This was
convincingly portrayed with data that showed that in order for
the life expectation of the French population, as well as the
populations of other developed nations, to increase there would
have to be a disproportionate decline in mortality. He pegged the
practical limit to mean life expectancy (LE) at birth in France
at about 85 which to be achieved would require a decline in
mortality of just over 50 percent. An important point made was
that although simple extrapolation of mortality/LE trends suggest
this to be attainable, such predictions do not consider the
biology of populations. For example, to reach an LE of 100, 18
percent of the population would have to live beyond 120 years
(the currently accepted 'limit' to human maximum life span
(MLS)). Consequently, such trends could only be maintained
following elimination of all cardiovascular diseases, cancer and
the other significant killers. He concluded that although there
is nothing we can do *today* to increase LE beyond 85 years, an
LE beyond 85 may be achieved if significant medical and
scientific breakthroughs were made that allowed successful
medical interventions in disease and deceleration of the basic
rate of ageing.

Next up was James Vaupel who began his discussion by boldly
stating that he believed that 'the average baby born in France
today will live to 95-100', his confidence apparently unshaken
by the previous speakers line of reason. However, I regarded the
ideas presented by Vaupel not to be too far removed from Jays
conclusion, since he expressed his deep belief that mortality
rates will continue their current rate of decline due to the
likelihood of future breakthroughs in science and medicine over
the lifetime of today's babies that will be of the same magnitude
as those seen during the last century. Quite rightly he exclaimed
that 'the future has proved to be not only unexpected , but to
be surprisingly unexpected'. He also presented data which
suggested that the recent increases in the probability of
reaching late ages (ie. 60, 85, 95) is increasing at a greater
rate for later ages. He regarded this and other results to
discredit the commonly held belief that death at older ages are
mostly intrinsic, and that its almost impossible to reduce
intrinsic causes of death.

Jacques Vallin then took a flight of fancy and speculated on the
consequences of a 150 LE and models of fertility on future
population size. Although I was not familiar with some of the
models he used I couldn't help but get the impression that their
complexity could not be justified by the apparent lack of raw
data. Nevertheless, some predictions made included a 'stable'
world population of 118 billion (150 LE/2.5 children per woman)
by the year 2315, more than double that predicted if LE is 85.
Also, age structure of a population with an LE of 150 would
result in <1 percent under age 20 while > 85 percent over 100
years old. 

The biological perspective of a limit to maximum life span (MLS)
presented by Tom Kirkwood brought many feet back down to the
ground but certainly did not rule out the potential of modulation
of senescence through biomedical interventions. Tom also
introduced the (so far neglected) evolutionary perspective of
_why_ ageing occurs and how this enables the question of _how_
ageing occurs to be answered. He explained that the optimisation
of reproductive fitness through the balance between somatic
maintenance and reproduction (the disposable soma theory) was
modulated by the expression of genes involved in maintenance of
the soma and whose combined force provided a particular
'longevity assurance' for that organism. He was of the opinion
that for any organism with a particular longevity assurance there
was an intrinsic limit to MLS in any given environment, but that
changes in these underlying genes either through selection,
transgenics, or  by changes in nutrition, exercise or biomedical
intervention may allow modulation of MLS.  

This was followed by a series of talks on the emergence of
centenarians and 'supercentenarians', the trends in their
mortality between the West and East (China), and broad
differences in their health presented by Jeune/Kannisto, Zeng and
Forette respectively. Then there was a special presentation of
the first ever Foundation IPSEN prize on Longevity, a new award
which each year will be given to a scientist in the field of
ageing and longevity, be he biologist, demographer or otherwise.
This year Caleb Finch collected the award in recognition for his
exceptional work on the neuroendocrinology of ageing, and his
seminal text on longevity, senescence and the genome.

During the lunch intermission I spoke with, Jay Olshansky about
his views on the possibility of significantly extending human
lifespan in the future. I was interested to find out that he
considers himself an optimist even though his research predicts
small improvements in LE. If any advances were going to occur
then he felt they would probably come from developments in
pharmaceutical and the creation of new drugs or medicines along
the same lines of Melatonin and DHEA. 

The presentation by Francois Schachter covered the goals and some
early results of the Chronos Project: the collection and analysis
of blood samples from centenarians to create a database of
certain characteristics strongly associated with long living
individuals. One interesting finding was that certain HLA types
are more common in centenarians than in controls, in particular
DR1, DR11, DR13 in male and DR7 in female centenarians. 

The concluding three talks began with Raj Sohals transgenic fruit
flies overexpressing both catalase and Cu-Zn SOD: two of the most
well characterised genes involved in oxygen free radical
scavenging. He found their joint effect to be much greater than
the effect of each gene  overexpressed on its own with extension
in MLS between 70-100 percent. More importantly there also
appeared to be an improvement in 'healthspan' with the flies
exhibiting greater mobility into old age, a delay in the onset
of the inability to fly and an improved response to X-ray

This was followed by discussion on the significant extension of
MLS of more than 100% in the nematode C. elegans by a mutant form
of a gene called age-1 by Tom Johnson. He explained that this
result is very exciting since in means we 'might be able to
significantly extend lifespan of even higher lifeforms (including
humans) by single gene manipulations'.  When questioned whether
he would expect to see lifespan extension in humans of the same
scale found in C. elegans he replied that he it is very possible
to achieve equally dramatic effects in humans and that although
development of the technology to accomplish this feat may take
5 years or 100 years, he sees it one day becoming a reality. He
had also found several other genes such as daf-2 and spe-26 which
produced similarly impressive results, and was near to cloning

The final speaker was tuck Finch who provided some interesting
insights into the causes of non-genetic variations in life span;
why there is a > five fold variation in lifespan among
genetically identical individuals maintained under identical
conditions. The main thrust of his argument was that random
events during early development set absolute limits to the
functional lifespan of certain organs. Included among these were
the initial size of the cell pools of oocytes (determining length
of reproductive period in females), neurons (determining the
threshold of neuron loss beyond which major dysfunctions emerge)
and stem cells from which immune cells are derived. This has
obvious implications for Alzheimers disease were there appears
to be great losses of neurons. One factors suggested to effect
cell pool size during development was influences from a
neighbouring fetus. Such limiting factors were observed in both
mice but not in C. elegans in which cell numbers are strictly
controlled to ensure each individual has the same amount, which
suggests mammals and lower life forms may differ in the origins
of these non-genetic variations in LS.

Generally, I found the conference to be a really great
combination of views  - many conflicting - and despite being only
one day a lot was covered. The conference will be repeated next
year and I hope to go again. Anyway, I hope some of the
discussions that took place at the Paris conference may be
continued on this list. 

Best regards,

Sam Cronin

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