From Science News Online

July 23, 2004

Here is the article from Science News without the pictures. If you

go to the sciencenews.org website, and scroll down their home page,

on the left sidebar you will see the article " Dying before Their

Time " with the pictures.

Thanks,

Greenwood

---------------------------------

Science News Online

Week of July 10, 2004; Vol. 166, No. 2

Dying before Their Time

Studies of prematurely old mice hint that DNA mutations underlie aging

With one look, you can usually tell whether someone is old or young.

Wrinkled skin or smooth. Thinning hair or thick locks. Bifocals or

Ray-Bans. These are just a few of the overt clues. Far less obvious

are the age-related signs that show up on the molecular level. Ask a

geneticist where to look and he may point you to a person's

mitochondria. These rod-shaped residents of an animal cell provide

the cell with energy, and each mitochondrion has its own DNA strand,

which is distinct from the DNA in the chromosomes that dwell in the

cell's nucleus. With age, this mitochondrial DNA (mtDNA) becomes

riddled with mutations, both subtle and severe.

[iMAGE] OLD STORY. Some researchers conjecture that the increasing

burden of DNA mutations in mitochondria, organelles that provide an

animal cell with energy, is a cause of aging.

& #169; Roseman/Custom Medical Stock Photo

This observation, made in many species, has prompted some researchers

to conjecture that the increasing burden of mutations in

mitochondrial DNA is a cause of aging. The majority of researchers

have thought otherwise. They argue that the mutations are molecular

consequences of aging, akin to wrinkles and graying hair.

" You get more gray hair as you get older, but nobody thinks aging is

caused by gray hair, " says Nils-G & #246;ran Larsson of Karolinska

University Hospital in Sweden.

Recently, however, Larsson and his colleagues have genetically

engineered mice to develop mtDNA mutations faster than normal.

Compared to typical lab mice, these rodents suffer age-related

conditions, such as hair loss, osteoporosis, anemia, and infertility,

much sooner than typical mice do, and they die young. Many scientists

hailed these results, reported in the May 27 Nature, as a vindication

of the mitochondrial theory of aging.

" We have been waiting for many years for experimental evidence like

this.... It is a fundamental advance in aging research, " says

s of Virginia Bioinformatics Institute in Blacksburg.

s finds the new report especially credible because several of

its authors, including Larsson, have been publicly skeptical about

the hypothesis that mtDNA mutations play a leading role in aging. For

example, in a commentary in the February 2003 Aging Cell, T.

s of University of Tampere in Finland challenged the evidence

implicating mtDNA mutations.

But the prematurely aging rodents have made him rethink his position.

" I must admit that our findings are provocative, " says s. " The

hypothesis that I confidently expected would fall, did not... The

mtDNA mutation theory of aging emerges from all this with something

of a feather in its cap. "

Some scientists aren't waiting for further confirmation. They're

already exploring ways of countering the potential effects of the

decay in mtDNA. A few researchers have even proposed genetically

engineering people to make their mtDNA less prone to mutations.

Cellular liaisons

At some early point in the history of life, two microscopic

cells & #151;most likely different kinds of bacteria & #151;apparently

struck a complex bargain. One provided a safe, comfortable home

inside its own cellular membrane. In exchange, the new tenants

produced extra energy for the host cell. The enveloped microbes

gradually shed their distinct identities and became what now are

called mitochondria.

Mitochondria are the power plants of an animal cell. Some

energy-hungry cells, such as those in muscles, contain up to a

thousand of these remarkable organelles. Instead of making

electricity, as conventional power plants do, mitochondria use oxygen

and complex sugars in a process known as respiration. The product is

an energy-rich molecule, adenosine triphosphate (ATP), which cells

use to drive myriad chemical reactions. Without ATP, cells would be

powerless and die.

A mitochondrion's minuscule anatomy incorporates more than 1,000

different proteins, but most of the genes encoding them have moved

into the more sheltered environment of the cell's nucleus. Remaining

within the mitochondrion itself, however, is a small loop of DNA

harboring 13 assorted genes. It is this DNA that some researchers

suspect may hold the keys to aging.

Because the mtDNA isn't sequestered in the nucleus, it's exposed to

potentially damaging molecules floating around the cell's cytoplasm.

What's more, mtDNA doesn't have the benefit of the repair enzymes

available to genes in a nucleus.

Also, the very work that mitochondria do may damage their DNA. The

act of creating ATP spawns toxic by-products called free radicals

that can rip nearby molecules to shreds. That, conceivably, could

underlie various aspects of aging.

" All cells depend on mitochondria for energy, and if the mitochondria

begin to fail, then you would expect to see a general slowing of

activity throughout all the cells of the body, " says s. " And

that description fits with aging. "

Another popular theory holds that aging results from the damage that

free radicals do to various molecules in a cell. Free radicals arise

not only from ATP production but also from other chemical reactions

in the cell. Indeed, one camp of researchers considers the

mitochondrial theory of aging a spin-off of the free radical

hypothesis. These scientists say that mtDNA is simply a target of the

free radicals.

Even so, everyone who studies the molecular basis of aging agrees

that mtDNA gets more and more scrambled as animals age. Some of the

mutations are subtle & #151;a simple change of a single nucleotide, the

basic building block of DNA. Others involve gross rearrangements of

the mtDNA sequence or deletions of large stretches of the molecule.

" It's a universal phenomenon, " says Larsson. " You find these

mutations in every aging human. You find [them] in mice, rats, and

monkeys. "

Life span limits

Highlighting the potential importance of mtDNA mutations, s

reports in the May Trends in Genetics that the vulnerability of mtDNA

to deletions may constrain the maximum life span of most mammals to

80 to 100 years. Analyzing previously reported mtDNA sequences of 61

mammalian species, he considered the number of DNA repeats, which are

nucleotide sequences that occur twice in close proximity along a DNA

molecules. Such repeats mark areas of mtDNA that tend to get deleted

with age.

s found that the species with the longer life spans generally

have the smaller numbers of certain DNA repeats. Therefore, surmises

s, " longer-lived species have mtDNA that is less susceptible to

mutation. "

s acknowledges that his findings provide at best

" circumstantial evidence " for the mitochondrial theory of aging.

That's why he is so impressed by the results of Larsson and s

and their colleagues.

Those researchers put the mitochondrial theory of aging to a direct

test by creating mice with a defective gene for the enzyme that

copies mtDNA. " This enzyme... has the capacity to proofread newly

synthesized DNA. If it makes an error, it can go back and insert the

right nucleotide, " says Larsson.

[iMAGE] GROWING OLD. Compared to a typical middle-aged mouse (top),

a mouse that is the same age but riddled with mutations in a certain

kind of DNA (bottom) has begun to show signs of premature aging. The

rodent has lost weight and developed a curved spine due to weakening

bones. Its hair has begun to go gray and fall out.

A. Trifunovic, et al./Nature

His group used genetic engineering to produce mice that have a

version of the enzyme that's sloppier than normal at proofreading. As

a result, deletions and other mutations rapidly accumulate in each

mitochondrion's DNA.

At birth, mice with this defective enzyme look and act healthy. Five

months into their lives, however, they already seem to be getting

old. They start to lose hair and weight and to develop osteoporosis,

which leads to a curvature of the spine. Their hearts enlarge, and

the mice become anemic and infertile. All of the rodents in Larsson's

study were dead within 14 months; in contrast, a typical lab mouse

lives 24 to 36 months.

" These findings strongly support the idea that mutations in

mitochondrial DNA can cause at least some features of aging, "

M. and Lawrence A. Loeb, both of University of Washington in

Seattle, conclude in a commentary accompanying the Nature report by

Larsson's group.

" It's a beautiful paper, " adds mitochondria researcher Clayton

of the Medical Institute in Chevy Chase, Md. " It will

be regarded as a classic. Their claim is warranted & #151;that this

[experiment] establishes a causative link between mtDNA mutations and

aging. "

That said, the new study leaves many questions unanswered. For

example, how does an increase in mtDNA mutations cause so many

aging-related problems? One possibility is that key cells may die or

fail to perform necessary duties as their mitochondria produce less

ATP. Another is that deteriorating mitochondria may, as they struggle

to make ATP, unleash a flood of extra free radicals that disrupt

other cellular functions.

" My hunch is that the higher mutation load results in a higher rate

of generation of reactive oxygen species or other toxic by-products

of respiration, but that will need to be painstakingly tested, " says

s.

Other researchers caution that although the recent study shows that

mtDNA mutations can cause premature aging in genetically altered

animals, it doesn't demonstrate that these mutations occur naturally

at a rate that produces aging.

" The real strength of the paper is that it establishes a causal

association between mtDNA mutations and accelerated aging, but what

it can't do is tell us precisely how much the natural variation of

aging is due to natural variation in mtDNA-mutation rates, " says

Rand of Brown University in Providence, R.I.

Nonetheless, the mice engineered by Larsson and his colleagues should

invigorate research into the processes of aging. " They've developed a

wonderful tool with enormous potential, " says Judd M. Aiken of

University of Wisconsin in Madison.

Aiken is interested in studying the muscles of the mutant mice. As

people age, their muscles gradually waste away in a phenomenon called

sarcopenia (SN: 8/10/96, p. 90:

http://www.sciencenews.org/pages/sn_arch/8_10_96/bob1.htm). Aiken's

team has amassed evidence that this deterioration occurs because more

and more mitochondria malfunction with age.

Larsson's team plans to cross the fast-aging rodents with mice

genetically engineered to produce increased amounts of an enzyme that

mops up free radicals in mitochondria. If the offspring live longer

than 14 months, it would solidify the presumed connection between

free radicals, mtDNA mutations, and aging.

Larsson envisions drug companies using the prematurely aging mice to

test compounds intended for treating or staving off osteoporosis,

sarcopenia, and other age-related conditions. " My goal is not to find

something to prolong life but to find something to reduce the

pathology of aging, " he says.

For others, prolonging life is the primary goal, and they see an

opportunity hidden in the mitochondrial theory of aging. Several

scientists, most notably Aubrey D.N.J. de Grey of the University of

Cambridge in England, have proposed a way to prevent the decay of

mtDNA, and thereby perhaps to prevent aging. They suggest

transferring copies of mtDNA's 13 genes into the safer environs of

the cell nucleus, where the rest of the mitochondrial genes reside.

" It's science fiction right now [but] imaginative, " says .

The case for the mitochondrial DNA theory of aging isn't closed. Some

facets of aging, such as cataracts and a weakening immune system,

haven't turned up in the new mutant mice. This implies that there are

multiple causes of aging.

Moreover, and Loeb contend that an ultimate test of the

mitochondrial theory of aging would be to create mice whose

DNA-copying enzyme is more accurate than normal. That should slow the

mtDNA-mutation rate and, if the theory holds, lengthen the lives of

the rodents.

The Climate Connection

Cold weather might have selected for life-prolonging stretches of DNA

Some scientists are looking among the 46 human chromosomes for genes

that promote longevity in people, but they may be looking in the

wrong place. C. Wallace of the University of California,

Irvine contends that he and his colleagues have found a potential

fountain of youth in mitochondrial DNA (mtDNA), the loops of genetic

material in mitochondria, the energy-producing organelles of human

cells.

" We're finding mtDNA variants that allow people to live longer, " says

Wallace.

Human mtDNA consists of 13 genes encoding proteins that enable

mitochondria to produce the energy-storage molecule adenosine

triphosphate (ATP) in a process known as cellular respiration. That

process also generates the heat that maintains body temperature. The

amount of heat made by mitochondria depends on their efficiency. The

better they are at making ATP, the less heat they generate.

Wallace and his colleagues have recently analyzed the mtDNA of more

than 1,100 people from around the world and concluded that some of

the differences result from adaptations to the local climate. After

comparing the mtDNA of people in tropical Africa to that of people in

temperate Europe and arctic Siberia, the researchers argue that

residents in colder climates have evolved mtDNA that produces

less-efficient mitochondria and so generates additional body heat.

" Different physiologies are good for different contexts, " notes

Wallace.

In the same report, published in the Jan. 9 Science, the researchers

assert that certain mtDNA lineages are associated with increased

longevity. These mtDNA variants, found among temperate European

populations, appear to produce mitochondria that generate more heat

than lineages in tropical Africa do, says Wallace. The more heat and

the less ATP that mitochondria make, the lower their production of

free radicals, the highly toxic molecules implicated in aging. So, in

theory, the mtDNA highlighted by Wallace should slow aging.

Wallace still has work to do to convince his colleagues. " The

interpretation that certain mtDNA variants produce more heat and are

thus evolutionary adaptations to northern climates is viewed with

skepticism, " says s of Virginia Bioinformatics Institute

in Blacksburg. The purported connection between certain versions of

mtDNA and longevity, he says, is a " very weak association

statistically. "

To convince his skeptics, Wallace plans to genetically engineer mice

to have mtDNA similar to the human versions that he argues promote

longevity. If those animals live longer, some of that skepticism

could wither away.

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References:

de Grey, A.D.N.J. 2000. Mitochondrial gene therapy: An arena for the

biomedical use of inteins. Trends in Biotechnology 18(Sept.

1):394-399. Abstract available at

http://dx.doi.org/10.1016/S0167-7799(00)01476-1.

s, H.T. 2003. The mitochondrial theory of aging: Dead or alive?

Aging Cell 2(February):11-17. Abstract available at

http://dx.doi.org/10.1046/j.1474-9728.2003.00032.x.

, G.M., and L.A. Loeb. 2004. Mice and mitochondria. Nature

429(May 27):357-359.

Mishmar, D.... and D.C. Wallace. 2003. Natural selection shaped

regional mtDNA variation in humans. Proceedings of the National

Academy of Sciences 100(Jan. 7):171-176. Available at

http://www.pnas.org/cgi/content/full/100/1/171.

Pak, J.W.... and J.M. Aiken. 2003. Mitochondrial DNA mutations as a

fundamental mechanism in physiological declines associated with

aging. Aging Cell 2(February):1-7. Abstract available at

http://dx.doi.org/10.1046/j.1474-9728.2003.00034.x.

Ruiz-Pesini, E.... and D.C. Wallace. 2004. Effects of purifying and

adaptive selection on regional variation in human mtDNA. Science

303(Jan. 9):223-226. Abstract available at

http://www.sciencemag.org/cgi/content/abstract/303/5655/223.

s, D.C. 2004. Mitichondrial DNA repeats constrain the life span

of mammals. Trends in Genetics 20(May 1):226-229. Abstract available

at http://dx.doi.org/10.1016/j.tig.2004.03.003.

Trifunovic, A.... H.T. s, and N.-G. Larsson. 2004. Premature

ageing in mice expressing defective mitochondrial DNA polymerase.

Nature 429(May 27):417-423. Abstract available at

http://dx.doi.org/10.1038/nature02517.

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