Living longer - Living better

[Samuel Cronin]

Having just returned from the three day 'Living Longer - Living 
Better' conference in Manchester this last week I thought some of the 
members of this group may be interested in the highlights. Admittedly, 
the short review below hardly gives a feel for all of what was 
discussed at the conference as I have purposefully biased my choice of 
speakers to those I am personally interested in and who I think will 
be of most interest to the readers of this group. 

The conference itself was very well attended by over 200 delegates 
with 124 poster presentations and 85 speakers whose talks were divided 
into parallel symposiums of either biological, clinical or social 
gerontology. The first two speaker summaries I have prepared are 
primarily concerned with the 'glycation theory of ageing' and possible 
interventions whereas the last two consider the antiageing effects of 
the only 'proven' method of extending lifespan - dietary restriction. 
I would also have liked to included a summary of the several 
discussions that took place concerning Werner's Syndrome and related 
topics such as the telomere hypothesis but I know there are far better 
qualified researchers in these areas than me on this list who were 
also at the conference, such as Richard Faragher and David Kipling, 
who may perhaps wish to comment.


Antony Cerami - Sugar-derived advanced glycation end products (AGEs) 
in circulation and tissues promote the adverse sequelae of ageing. 
======================================================================

Antony Cerami began by summarising the historical evidence for the 
accumulation of advanced glycation end products (AGEs) derived from 
the reaction of reducing sugars such as glucose with proteins, lipids 
or nucleic acids (the glycation theory of ageing). He also provided 
some evidence for the role of AGEs in disease, including experiments 
where AGE peptides injected into rodents or rabbits caused many of the 
complications of diabetes (accelerated atherosclerosis etc.) as well 
as the generation of B-amyloid plaques in the brain.

Antony explained that although the structure of several AGEs have been 
proposed there was no agreement which ones were most important in the 
adverse effects of ageing. Nevertheless, he proposed that a new AGE 
molecule called an ene-dione discovered in his lab had the potential 
to be the most common AGE produced in ageing, and hence perhaps the 
most important. 

Prevention of AGE formation in rat models has long been achieved by 
the use of aminoguanidine, however, Antony's group had discovered that 
the B vitamin thymine can react with the specific AGE protein-
crosslink associated with the ene-dione structure and actually 
separate the proteins, essentially reversing cross-linkage. Tests 
showed that thymine uncrosslinked 80% of all AGE-linked Ig and red 
blood cells, suggesting that the other known AGE structures (eg. FFI, 
pyraline etc) may be less important. Experiments testing the 
effectiveness of thymine at reversing crosslinking are continuing 
(presumably also crosslinkage between lipids and nucleic acids), and 
the latest results indicate thymine is also effective at 
disaggregating the amyloid plaques associated with Alzheimer's 
disease.



JE Preston - B-Amyloid and AGE-protein toxicity in endothelial cell 
culture of the rat blood-brain barrier
======================================================================

Continuing the theme of Alzheimer's disease, Preston described the B-
amyloid toxicity on the blood-brain-barrier following accumulation of 
these plaques in the endothelial cells lining the blood vasculature of 
the brain. The transfer of nutrients to the brain is hindered and have 
reduced glucose uptake and lactate production  In addition Preston 
found endothelial cells cultured with B-amyloid have only about 40% 
survival which is thought to be due to a generation of a hyperoxic 
state leading to massive lipid peroxidation. 

Preston decided to investigate whether the naturally occurring 
dipeptide carnosine (B-alanyl-L-histadine), which has been reported as 
having both antioxidant and antiglycosylation effects, could protect 
against amyloid toxicity. He found carnosine allowed 100% survival of 
endothelial cells when exposed to B-amyloid, as well as improving 
glucose uptake and lactate production. In addition, the metabolites of 
carnosine, B-alanine and L-histadine also improved survival (in 
particular B-alanine). He also found that carnosine provided a greater 
protective effect than SOD or glutathione. The concentrations used in 
his experiments found a protective effect from carnosine 
concentrations of 20mM and above in neuronal tissue.


Ed Masoro - A biological evaluation of dietary energy intake and the 
ageing of laboratory rodents
======================================================================

Ed Masoro (University of Texas) began his presentation by first asking 
the question "what is the specific item which when restricted slows 
ageing?". Restricting only fat in rats in his lab led to no difference 
in life span compared to isocaloricaly fed controls, and protein 
restricted rats fed in the same way also exhibited no change in life 
span. In fact he found no particular item led to improvements in life 
span except the absolute caloric (energy) intake, leading to his first 
conclusion that reduced energy intake is the dietary factor involved 
in the life extending effects of dietary restriction (DR). 

The next question he had set out to answer was whether the effect of 
DR was to actually slow ageing or just to postpone the onset of sexual 
maturity which would only give the impression of a slowed rate of 
ageing. He fed four groups of rats either (1) ad libitum, (2) DR all 
through life, (3) DR from birth to sexual maturity and (4) DR from 
sexual maturity to death and compared their maximum life spans (MLS). 
Groups 2 and 4 were the longer lived with MLS of 1295 and 1298 days 
respectively while groups 3 and 1 came a distant second, leading 
Masoro to rule out any effect of DR working via slowing fertility 
onset.

He also compared the life extending effect of DR on lean and obese 
mice and although no  statistically significant difference was found 
he did note that if anything the obese rats lived longer! Another 
unexpected discovery was that metabolic rate/unit of lean body mass of 
DR and normal rats was the same as was O2 consumption. However, their 
was much lower 24 hour plasma glucose levels in DR rats as well as 
lower maximum levels of insulin compared to ad libitum fed rats which 
suggested DR rats could utilise glucose with less insulin by either 
increasing "insulin sensitivity" or "glucose utilization 
effectiveness" or both.

Comparing the response of DR and normally fed rats to several 
stressors found DR rats to be far more resistant. Recovery after 
surgery was faster (and the amount of weight loss less) in DR rats, 
and they also showed a much quicker immune response to antigens. 
Survival following heat shock was 16% in ad libitum fed rats compared 
to 70% in DR rats which were also showed to have a greater expression 
of heat shock protein hsp70. Ed Masoro concluded that the changes that 
occur during DR have evolved to cope with increased stressors and not 
to slow ageing, although the antistressing effect directly leads to an 
antiageing effect. 


Axel Kowald - Life extension through diet: evolutionary implications
====================================================================

Axel's mathematical model for the observed antiageing effects of 
dietary restriction appeared surprisingly simpler than some of his 
previous models (his last paper on the Network Theory of Ageing 
contained literally hundreds of variables), however, most of the 
predictions of the model fitted experimental observations quite well. 
The theoretical basis for the model derived from evolutionary biology 
(Disposable Soma Theory: Kirkwood) which in a nutshell and highly 
simplified states that the energy (food) entering the organism is 
shared between somatic maintenance (repair processes etc), growth and 
reproduction in such a way that maximises the number of surviving 
offspring. 

             Growth
Energy ----> Maintenance  ----> progeny
             Reproduction

The optimal allocation of resources depends on the environment (ie. 
food availability) and can be calculated using the 'Lotka equation' 
which describes the ideal input into maintenance and reproduction for 
maximising progeny in a given environment. The Lotka equation also 
contains an expression 'r' which relates to the mortality rate 
doubling time (MRDT) or the rate of ageing and thus by altering the 
environment the equation predicts changes in the pace at which ageing 
occurs.  

In humans the MRDT is about 8 years after sexual maturity (ie. every 8 
years your risk of dying from any particular intrinsic cause of death 
doubles), however, by simulating famine conditions using an extended 
version of the Lotka equation the model predicts an increase in the 
MRDT which is dependant on the severity of starvation. As far as I 
could tell the model didn't predict the optimum degree of starvation 
to obtain the highest MRDT, although it did predict greater 
improvements in longevity the earlier DR is started with diminishing 
benefits in later life. Even brief periods of 10 days of severe DR was 
predicted by the model to have marginally beneficial effects on MRDT 
which may be relevant in terms of the effects of fasting. Overall the 
model agreed well with experimental observations with both average 
life span and maximum life span being increased during DR and the 
extent of this effect depending on the length and severity of dietary 
restriction. 

***

Considering this was the first British congress of gerontology ever 
the organisers saw it as a quite a landmark in British gerontological 
research. Speaking to Tom Kirkwood, one of main the organisers of this 
congress, he said that judging by the interest and success of this 
first congress we can expect another next year in what may become an 
annual event taking place in different locations throughout the UK. 
Newcastle is strongly tipped to be next years location and as soon as 
I know more information I could post the registration details to this 
group if anyone is interested in attending.

All the best,

Sam Cronin

***I will be away from my terminal for two weeks after July 16 and 
only intermittently thereafter during the summer*** 
~