Exercise benefit for some questioned

[Guest guest]

Hi All,

Some CRers have higher levels of lipids thought to be

associated with better health than others. A good example

is Saul, who does not CR as much as many of us do. This

appears not to be due to any particular unique feature of

his CRON diet.

Do our benefits from exercise depend on our genes?

Exercise increases levels of high density lipoprotein

(HDL) and an enzyme called angiotensin-converting

enzyme (ACE). The article from Nature not in Medline

yet indicates that our benefits from exercise are

dictated by genes regulating the level of these molecules.

Nature 433, 188 - 189 (20 January 2005)

Alison Abbott

All pain, no gain?

Exercise is good for you, or so we always thought. But, as Alison

Abbott learns, your genes don't always cooperate.

When Claude Bouchard set out to see whether genes play a role in

physical fitness, he assumed, like most people, that exercise

training makes everyone fitter. Although he expected genes to

modulate some individual responses to diet and exercise, he also

anticipated that regular workouts would improve fitness indicators

such as lung efficiency and blood cholesterol for everybody.

Some 20 years later, it has become clear from the work of Bouchard

and others that this is not the case. Looking at certain measures of

fitness, some people actually fare worse after exercise, whereas

others show little or no improvement.

But this isn't vindication for couch potatoes. Everyone's health

improves in some way or other from exercise, but just how it improves

is largely dependent on genes. Now, the growing field of fitness

genetics is attempting to tease those genetic components apart, and

the studies are generating fresh insights into the benefits of

exercise as well as unexpected pay-offs for medicine.

Bouchard's attempts to track fitness genes began in the mid-1980s

at Laval University in Quebec, Canada. He and his colleagues focused

on the maximum amount of oxygen absorbed by the body from a lungful

of air — a standard measure of aerobic fitness, usually abbreviated

as VO2max. They found that most people can get more oxygen out of

each breath after training but that a minority were no better off,

regardless of how efficient their lungs were at the start. Because

the variation was much less extreme within pairs of identical twins,

Bouchard concluded that the effect was largely dictated by genes1.

" Our work on athletes is feeding back into the clinic. How

efficiently we use oxygen is decisive when we are desperately sick. "

That initial study was fairly small, so Bouchard extended the

work in 1992 by helping to set up a multicentre research effort

called the HERITAGE Family Study, which is still running today. Now

based — together with Bouchard — at the Pennington Biomedical

Research Center in Baton Rouge, Louisiana, the study's main data set

comes from some 740 sedentary adults who were subjected to an intense

exercise regime in the lab. The researchers monitored changes in the

participants' blood pressure, heart rate, blood chemistry and VO2max

over 20 weeks.

Survival of the fittest

The study's main aim was to determine how exercise reduces risk

factors for cardiovascular disease and diabetes, but Bouchard and

researchers at the four other collaborating institutions also took

blood samples for genetic analysis. " We were trying to find as many

genes as possible that influence fitness and performance, " Bouchard

says.

The resulting reams of data and frozen blood samples are still

being analysed, but the results so far confirm Bouchard's earlier

studies. The average increase in VO2max after the training programme

was 19%. But 5% of the subjects had virtually no change, and another

5% had improved by more than twice the average amount. Similarly,

most people had lower exercising heart rates and blood pressure after

the training programme — an indication of improved fitness — but the

extent of the reduction was extremely variable. In a few people there

was even a small rise in these numbers2.

Much of this variability seems to be attributable to genes. The

researchers found more variation between than within families,

suggesting at least a portion of a person's ability to benefit from

exercise is inherited. " We concluded that just about half of the

difference in trainability was heritable, " says Tuomo Rankinen, the

study's project manager.

It is unclear to what extent fitness parameters such as VO2max are

indicative of long-term health prospects, but even presumed health

indicators such as cholesterol, a factor in heart disease, did not

follow the expected pattern of more exercise is better. Conventional

wisdom has it that regular exercise reduces the risk of heart disease

by raising blood levels of high-density lipoprotein (HDL)

cholesterol, a complex that helps prevent cholesterol from forming

fatty deposits on blood-vessel walls. This is considered one of the

key benefits of taking up sports such as running. But the HERITAGE

data show that training does not inevitably increase levels of HDL

cholesterol. In fact, in about one-third of exercisers, the level of

the complex fell.

Does this all mean that exercise could actually be bad for those

of us with the 'wrong genes'? Not at all, insists Rankinen. " We found

not a single 'universal non-responder', " he says. In other words,

everyone improved on some score. Even those who could not raise their

VO2max through exercise were still getting some other health benefit

such as higher HDL cholesterol levels or lower blood pressure. And

overall, the HERITAGE data show that the risk of cardiovascular

disease and type 2 diabetes falls in those who exercise regularly,

Rankinen says.

One way to begin to untangle these apparently contradictory

effects is to go after the genes involved. This could ultimately

reveal a great deal about how exercise produces health benefits, and

may lead to treatments for diseases of metabolism and physiology.

To this end, scientists at the HERITAGE study are scanning the

genomes of participants for gene variants that occur more frequently

in association with different fitness responses. Although some

metabolism genes have been identified that may play a role, the most

strongly linked gene so far is Titin. This produces protein fibres

that contribute to the elasticity of heart muscle cells. It may be

that some forms of the gene allow the heart to pump larger volumes of

blood than others3.

Physical attractions

Other teams are also on the hunt for fitness genes. ,

a health researcher at the Lawrence Berkeley National Laboratory in

Berkeley, California, for instance, suspects that a gene related to

the synthesis of HDL cholesterol might be involved. Ten years ago, he

found that people who have an easier time taking up running after

leading sedentary lives also started out with higher levels of HDL

cholesterol in their blood — and increased those levels more quickly —

than those who find running difficult4. It turns out that an enzyme

that boosts HDL cholesterol is found in 'slow-twitch' muscle fibre,

the type that takes longer to fatigue and so makes distance running

easier. is now beginning a large-scale genetic study to see

whether differences in that enzyme are associated with differences in

lifestyle choice.

Meanwhile, Gaston Beunen, a sports scientist at the Catholic

University of Leuven in Belgium, is looking at the half-dozen or so

key genes that contribute to the synthesis of myostatin, a protein

that blocks new muscle growth. His study of some 300 young sibling

males, published in May last year, hints that three of these genes

may help to determine a person's physical strength5.

In the end, the number of fitness-linked genes is expected to be

large. So far, more than 100 appear in the literature, most of which

have been identified in the past four years6, although in many cases

more work is needed to confirm the link. And some of these now seem

likely to prove their worth in the clinic.

One gene drawing a lot of attention encodes an enzyme called ACE,

or angiotensin-converting enzyme. ACE activates the hormone

angiotensin, which helps to maintain blood pressure and promotes the

growth of the heart in response to exercise. One common gene variant,

known as ACE D, makes more ACE than the other common version, ACE I.

And athletes who have inherited ACE D from both parents experience

about three times more heart growth in response to exercise than

those who have inherited two ACE I genes7. They also seem to perform

better in sports that rely on sheer strength and power, such as

weight-lifting or sprinting. The I variant, in contrast, is more

common among élite athletes in endurance sports such as long-distance

running and swimming, which require more efficient metabolic use of

energy and oxygen8, 9.

As the lower levels of ACE associated with ACE I improve

endurance, Hugh Montgomery, a cardiovascular geneticist at University

College London, wondered whether ACE I might also be advantageous to

those suffering serious illness. He found that children with

potentially deadly meningitis were more likely to require intensive

care or to die if they had two copies of the ACE D gene rather than

two copies of ACE I10. His team also found that premature babies with

ACE I fare better11. " Our work on athletes is feeding back into the

clinic, " says Montgomery. " How efficiently we use oxygen is decisive

when we are desperately sick. "

It may eventually be possible to help such patients with drugs

that slow down ACE activity. Already, in unpublished work, ACE

inhibitors have been shown to reduce muscle wasting in mice. And

London-based drug company Ark Therapeutics is currently running final-

stage clinical trials on the use of the ACE inhibitor imidapril to

treat severe muscle wasting in cancer patients.

" Genetic destiny should not become a new excuse for couch

potatoes — everyone gets at least some benefit from regular

exercise. "

Fitness genetics may be feeding ideas into the clinic, but could

genetic destiny become a new excuse for couch potatoes? " If they

think their performance is limited by their genes, people tend to

give up, " says Montgomery. " People are afraid of trying and failing —

it's part of the human condition. " Nevertheless, his advice to those

who long to be fitter is to do serious exercise come what may. For

everyone, it seems, there is at least some benefit.

References

1. Bouchard, C., Dionne, F. T., Simoneau, J. A. & Boulay, M. R.

Exerc. Sport Sci. Rev. 20, 27-58 (1992). | PubMed | ChemPort |

2. Bouchard, C. & Rankinen, T. Med. Sci. Sports Exerc. 33 (Suppl.),

S446-S451 (2001). | PubMed | ChemPort |

3. Rankinen, T. et al. Physiol. Genom. 15, 27-33 (2003). | ChemPort |

4. , P. T., Stefanick, M. L., Vranizan, K. M. & Wood, P. D.

Metabolism 43, 917-924 (1994). | Article | PubMed | ChemPort |

5. Huygens, W. et al. Physiol. Genom. 17, 264-279 (2004). | ChemPort

|

6. Perusse, L. et al. Med. Sci. Sports Exerc. 35, 1248-1264 (2003). |

PubMed | ChemPort |

7. Myerson, S. G. et al. Circulation 103, 226-230 (2001). | PubMed |

ChemPort |

8. Nazarov, I. B. et al. Eur. J. Hum. Genet. 9, 797-801 (2001). |

Article | PubMed | ChemPort |

9. Tsianos, G. et al. Eur. J. Appl. Physiol. 92, 360-362 (2004). |

PubMed | ChemPort |

10. Harding, D. et al. Am. J. Respir. Crit. Care Med. 165, 1103-1106

(2002). | PubMed |

11. Harding, D. et al. J. Pediatr. 143, 746-749 (2003).

Cheers, Al Pater