Root molecular cause of declining health in the old found by scientists

Feb 10, 2011 By Bill Schaller
Harvard scientists found that the basic cause of age-related health decline is malfunctioning telomeres — the end caps on cells’ chromosomes that protect them against DNA damage. Credit: Kris Snibbe/Harvard Staff Photographer

Scientists at the Harvard-affiliated Dana-Farber Cancer Institute say they have identified the root molecular cause of a variety of ills brought on by advanced age, including waning energy, failure of the heart and other organs, and metabolic disorders such as diabetes.

“What we have found is the core pathway of aging connecting several age-related biological processes previously viewed as independent of each other,” said Ronald A. DePinho, senior author of a report posted online by the . The first author, Ergun Sahin, is a member of the DePinho Lab and an instructor in medicine at Harvard Medical School (HMS).

DePinho, who is the director of Dana-Farber’s Belfer Institute for Applied Cancer Science and also a professor of medicine at HMS, said that although the studies were conducted in mice, “The findings bear strong relevance to human aging, as this core pathway can be directly linked to virtually all known genes involved in aging, as well as current targeted therapies designed to mitigate the toll of aging on health.”

The scientists found that the basic cause of age-related health decline is malfunctioning telomeres — the end caps on cells’ chromosomes that protect them against DNA damage. As cells reach their predetermined limit of times that they can divide, the telomeres become shortened and frayed, making the chromosomal ends vulnerable to increased rates of unrepaired DNA damage.

Faced with this increasing reservoir of injured DNA, cells activate a gene, p53, that sounds an alarm and shuts down the cells’ normal growth and division cycle, ordering them to rest until the damage can be repaired or, if not, to self-destruct.

Scientists previously had blamed this emergency shutdown and cell death for age-related deterioration of organs whose cells divide rapidly and are rejuvenated by reserves of adult stem cells. Such tissues include skin, intestinal lining, and blood cells, among others, which generate trillions of new cells each day of life.

However, left unanswered is how cells with less cell division, such as the heart or the liver, sustain equivalent levels of aging. The scientists felt if they could solve this mystery, they might gain new insights into how DNA damage could lead to age-related decline across all organs.

The new findings demonstrate that the telomere dysfunction and activation of p53 also trigger a wave of cellular and tissue degeneration that links telomeres to well-known mechanisms of aging that are not simply related to rapid growth and division. In other words, telomere dysfunction is not just one culprit in the declining health of advanced age. It’s the kingpin, according to DePinho and his colleagues.

DePinho published a study in Nature in January 2011 that demonstrated it was possible to reverse the symptoms of extreme aging in mice by increasing their levels of telomerase, the enzyme that maintains the health of the telomeres.

In this new, larger role, the telomere dysfunction also sets off an array of reactions leading to diminished health and longevity. For example, muscles suffer a loss of mitochondria, a cell’s chemical power plant, causing waning vitality and failure of the heart and other organs. Risks of metabolic disorders such as are increased.

In addition, the process weakens the body’s antioxidant defenses against the damaging molecules known as reactive oxygen species, or “free radicals,” that accumulate with age and exposure to stress. Until now, some researchers had labeled the decline in mitochondria or the buildup of free radicals as the primary causes of age-related ills. The new work integrates these seemingly disparate mechanisms into one unified theory of aging.

Telomere dysfunction causes this wave of metabolic and organ failure, the scientists found, because when the p53 gene is activated, it represses the functions of two master regulators of metabolism, PGC1-alpha and PGC1-beta. This dialing down of the regulators diminishes metabolic processes needed to provide energy and resist stress. In the mouse experiments, the scientists showed that “knocking out” p53 in mice released the brakes on PGC1-alpha and PGC1-beta.

“This is the first study that directly links telomere dysfunction to regulators of the mitochondria and antioxidant defense via p53,” DePinho said. “The discovery of this new pathway of aging integrates a lot of different ideas people have had and gives us a better understanding of the aging process.”

By unifying several major pathways of aging under the umbrella of telomere dysfunction, he said, the findings may yield new targets for therapies. The discoveries also may underlie the relatively sudden and rapid failure of the body leading to the end of life.

“Because telomere dysfunction weakens defenses against damage by free radicals, or reactive oxygen species,” DePinho said, “we think this exposes telomeres to an accelerated rate of damage which cannot be repaired and thereby results in even more organ deterioration. In effect, it sets in motion a death spiral.”

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User comments : 45

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Nikola
4.5 / 5 (25) Feb 10, 2011
With science there is no end to what we can achieve. Children being born today may live for hundreds of years. Overpopulation? Yes, but saving countless brilliant minds from death may also result in an increase in the pace of scientific discovery and progress that could accelerate our leap off this planet...or not. It's something that must eventually be confronted.
Donutz
5 / 5 (23) Feb 10, 2011
And if people believe they might be around in a hundred years, they might actually care a little more about the future of the planet.
Glyndwr
2.8 / 5 (22) Feb 10, 2011
With science there is no end to what we can achieve. Children being born today may live for hundreds of years. Overpopulation? Yes, but saving countless brilliant minds from death may also result in an increase in the pace of scientific discovery and progress that could accelerate our leap off this planet...or not. It's something that must eventually be confronted.


Overpopulation is a overhyped
ereneon
4.3 / 5 (9) Feb 10, 2011
Knocking out cell death genes can also lead to cancer, since cells with corrupt DNA can turn cancerous if not taken care of. Using p53 knockout or suppression in humans would probably not be a viable treatment. If they could do something to stop the telomeres from degrading in the first place, then we would really be getting toward a usable treatment. Great work though!
Eric_B
3.5 / 5 (13) Feb 10, 2011
"Overpopulation is a overhyped"

Sure is...

With mass-production of tunnel boring machines there is so much more cubit footage available underground for housing...use upstairs for growing food.
Skeptic_Heretic
3.9 / 5 (11) Feb 10, 2011
"Overpopulation is a overhyped"

Sure is...

With mass-production of tunnel boring machines there is so much more cubit footage available underground for housing...use upstairs for growing food.

There is that matter of fresh water to contend with, then you have a phosphorous problem immediately afterwards to contend with.
Moebius
2.9 / 5 (14) Feb 10, 2011
I believe longer lifespans up to and including physical immortality can only benefit us in the long term. We will be more likely to face problems if we think we will be around to be affected by them and that includes overpopulation.

There are 2 paths to possible immortality. I believe it is possible. The first would be one that changes those now alive to become immortal. The second and more feasible is changing our genes so that our offspring are immortal. I much prefer the former but if it is only the latter we will do it regardless of the naysayers and the religious who will try to stop it.

The first option may come about in steps starting with slowing or halting aging. I intend to stick around as long as possible for that to happen because I believe that it will happen this century or not at all. The final step which may take longer will be the reversal of aging.

I think that we will know almost everything there is to know about fundamental biology by the end of this century.
bg1
3.8 / 5 (5) Feb 10, 2011
Knocking out cell death genes can also lead to cancer, since cells with corrupt DNA can turn cancerous if not taken care of. Using p53 knockout or suppression in humans would probably not be a viable treatment. If they could do something to stop the telomeres from degrading in the first place, then we would really be getting toward a usable treatment. Great work though!


Even better is a way to restore the telomeres to increase the number of cell divisions. Furthermore, if population of cells could be built back up to youthful levels, then an old person could be transformed into a young person.
cwu
1.3 / 5 (7) Feb 10, 2011
On the other hand, being immortal could remove the sense urgency to get things done. Why hurry when you have all of eternity?
trekgeek1
3.5 / 5 (6) Feb 10, 2011
Necessity is the mother of invention AND action. If we extend our lives to hundreds of years, we will realize the need to control our breeding rates and environmental impact. If you know you can live for 300 years, you may not choose to have children for 150 years or more. Just because we can live longer, doesn't necessarily mean we will have a population emergency. It will speed up, but it may be manageable. And as bad as it sounds, third world countries probably won't have access to this, so only a small percentage of humans will have this life expectancy. Perhaps this is a natural control though since third world citizens have too many children. With the change in breeding mentality comes advancements in science, followed by extended life. In a sense, you don't understand how to extend life expectancy and live longer until you've matured your society to the point where it can handle such advancement.
Skeptic_Heretic
4.2 / 5 (6) Feb 10, 2011
On the other hand, being immortal could remove the sense urgency to get things done. Why hurry when you have all of eternity?
Living forever doesn't guarantee living well forever.
GSwift7
1.9 / 5 (13) Feb 10, 2011
And if people believe they might be around in a hundred years, they might actually care a little more about the future of the planet


I doubt it. People tend to become less idealistic as they mature.

Human lifespan has roughly doubled in recent history. Do we care more about the planet now than people did when they only lived half as long?

It will surely lead to people staying in top positions longer, making it harder for young people to advance in their careers though, which may widen the divide between the very wealthy and the rest of us.
ECOnservative
1.8 / 5 (5) Feb 10, 2011
So, in fixing telomere dysfunction might we be opening up a pathway for new cancers at the same time? Did I miss something?
Deadbolt
1.8 / 5 (10) Feb 10, 2011
I don't want to live forever, but my dream is to not age. It would be more awesome to remain young and healthy for 150-300 years, and then have a countdown start to my death, whereupon reaching zero; I promptly explode.
zevkirsh
1.8 / 5 (5) Feb 10, 2011
the only saving grace for the slave classes is that the rich die, and the stubborn lose their grip on power. if the rich could suddenly purchase another 40-80 years of healthy life. then 82 year olds like hosni-mubarak would have every incentive to increase repression and further tighten their grip on power. this would either lead to worse conditions for the world by way of more repression, or by way of more anarchic revolution by the masses. either way, extreme increase in lifespan (50% + in healthy years....living up to age 160?!) for those who can afford the new medications, will change the political world for the worse. perhaps the saving grace would be that it would hasten the arrival of one world government ruled by an uber-elite caste comprised of thousands of centenarian billionaires. running things in each region, and perhaps putting an end the ever-present threat of world war and globally catastrophic nuclear destruction.
Eric_B
2.8 / 5 (4) Feb 10, 2011
Hmmm...

Yeah, one of the drawbacks I imagine along the lines also mentioned, youth as underclass.

Imagine kids so frustrated they do drive-by shootings of us wealthy geezers...
droid001
1.7 / 5 (3) Feb 10, 2011
It is a simple way to be immortal. Save and transfer our memories to new bodies. Memories occupies very little space in the brain, therefore should not be a big problem.
googleplex
3 / 5 (4) Feb 10, 2011
It is a simple way to be immortal. Save and transfer our memories to new bodies. Memories occupies very little space in the brain, therefore should not be a big problem.

Backups of brains is estimated to be available in 2035-45 [Kurzweil et al.]. Once a back up is done then it does not matter when a simulator becomes available in the future. This is based on MRI resolution advances, data storage and processing power which exponentially increase by approx Moores Law.
PPihkala
not rated yet Feb 10, 2011
Google for TA-65. It's stuff used to lengthten telomeres. So the recipe for longer living is here already. But it's not cheap. If I remember correctly, I think it was 2000 USD for a half a year, which is much cheaper than it used to be, they tell (20000 USD).
maxcypher
3 / 5 (2) Feb 10, 2011
If you could be a cool, young go-getter for a 150 years, wouldn't you put off having little bambinos during that time? Perhaps the decision to have offspring would be more conscious and pro-active in that context. BTW, I think this is one of the more productive and on-point threads I've seen on this site.
TheGhostofOtto1923
3.7 / 5 (18) Feb 10, 2011
There are 2 paths to possible immortality. I believe it is possible. The first would be one that changes those now alive to become immortal. The second and more feasible is changing our genes so that our offspring are immortal.
If we can arrest the aging process, at what age would we choose to be for life? Would we necessarily want to be 'adult' at 30, or 25? Would being an adult command the respect it once did, if the people you worked for or chose as leaders were 70yo with the visage of adolescents?

I think most people would choose to be adolescent, and would eventually choose to discard those troublesome reproductive systems which cause the species so much anguish, as we become able to outsource the process. I think we will end up looking like the greys.
FrankHerbert
1 / 5 (3) Feb 10, 2011
On the other hand, being immortal could remove the sense urgency to get things done. Why hurry when you have all of eternity?
Living forever doesn't guarantee living well forever.


It's fairly naive to believe that we will be able to sort out the problems that cause death but those little nagging things that affect quality of life would be intractable problems. We'll fix senility and incontinence (oh no I crapped my pants, life just isn't worth living!) before average life span gets too out of hand. No one is going to be crapping their pants for the last 500 years of their life. What a silly thought.
brianweymes
4 / 5 (4) Feb 10, 2011
There's too much unbridled escapism here. Some of you are acting like an immortality medicine is mere decades away when really it could be centuries and centuries. I definitely wouldn't bet the farm on Kurzweil, who keeps having to revise his estimates, always being "off by a few years". Future economic recessions/depressions, war, famine/drought, environmental ruin, could all delay or derail modern civilization's scientific progress. Even if radical life extending technologies became available this century will the majority of humanity have access to them or will it only be for the rich? If so, couldn't this exponentially compound inequality in the world and contribute to instability? The consequences are unpredictable.
Moebius
1 / 5 (5) Feb 11, 2011
And if people believe they might be around in a hundred years, they might actually care a little more about the future of the planet


I doubt it. People tend to become less idealistic as they mature.

Human lifespan has roughly doubled in recent history. Do we care more about the planet now than people did when they only lived half as long?

It will surely lead to people staying in top positions longer, making it harder for young people to advance in their careers though, which may widen the divide between the very wealthy and the rest of us.


Wrong on every point.
lewando
1.6 / 5 (7) Feb 11, 2011
War will always remain the great regulator of "immortality".
mg1
not rated yet Feb 11, 2011
One thing is true of all things...equilibrium.

We live longer-population escalates, we wipe out all life on the planet.

How many people have hanging on there walls pictures of extinct animals we made extinct. Do the dutch care they wiped the dodo out. Do Americans care they wiped out pretty much every species in their country. Nope. Just think if you had them living forever. They wouldnt care aboyut anything.
TheGhostofOtto1923
3.3 / 5 (23) Feb 11, 2011
One thing is true of all things...equilibrium.

We live longer-population escalates, we wipe out all life on the planet.

How many people have hanging on there walls pictures of extinct animals we made extinct. Do the dutch care they wiped the dodo out. Do Americans care they wiped out pretty much every species in their country. Nope. Just think if you had them living forever. They wouldnt care aboyut anything.
Where do you live so we can make war on you please?
ormondotvos
4.5 / 5 (2) Feb 11, 2011
The USA, of course. Which demonstrates that the human race isn't sufficiently developed socially to expand (woo-woo!) out into space.

That's really the kind of spaced-out thinking that gets us into these messes.

In fact, we're humans, we have flaws and undeveloped capacities for cooperation that are currently suppressed by the idiotic idea that competition solves everything- the "invisible hand" that so often has an extended middle finger pointed at every other country, race, age, religion and culture.

Pull your head out of the sky and work on what's real and important.
kevinrtrs
1.3 / 5 (12) Feb 11, 2011
You can live as long as you like but unfortunately you'll still have to deal with the age-old problem of crime and violence. People not being satisfied with their lives and what they have and wanting to dominate others. In short - the story most people do not want to hear: you have to deal with SIN before you can even begin to contemplate living forever.
TheGhostofOtto1923
3.8 / 5 (20) Feb 11, 2011
Nonsense Kevin, if we no longer have to fear death and, I assume, we would be living in an automated society which could supply us with most anything we needed, there would be no need to grab more than you need at the moment. That's what greed is- a desire to save up for an uncertain future. And there would be even less need for your religions, which feed off the fear of death and ones fellow man.

Automation will make crime impossible and unnecessary. Medicine that makes us immortal will also correct all the neurological deficits we were born with or prevent them altogether, and repair them as we go along. We will have no compulsions, no delusions, no unnatural lusts, etc.

In short there will be no sin. We will have eaten of the tree of life and can thus do away with all lesser gods. Haha! I'm just funnin with ya.
murray
not rated yet Feb 11, 2011
Seems to be a lot of chickens being counted here....
Skeptic_Heretic
4 / 5 (3) Feb 12, 2011
You can live as long as you like but unfortunately you'll still have to deal with the age-old problem of crime and violence. People not being satisfied with their lives and what they have and wanting to dominate others. In short - the story most people do not want to hear: you have to deal with SIN before you can even begin to contemplate living forever.

Sin doesn't exist, criminals do. Deal with the real problem before inventing false dragons, or else you may end up attacking the windmills of your own argument.
StandingBear
1.8 / 5 (5) Feb 13, 2011
Now I suppose that the drug that knocks out P53 will become very patented, copyrighted, and trademarked before being handed to the Chinese pharm company that will make it for almost nothing. Then the verrrry expensive ideological child of Al Gore (name fits..he gored the whole world with his DMCA, and beggared the United States workers in particular) will go on to extort money from the moneyed all over the world without regard to morals or ethics. Now the ones that will live forever will be soulless monopolists, tinpot dictators, conniving politicians, silicone princess movie 'stars' and similar wastes of skin. The rest of us will get 'death with dignity'. The Muslims may be right about us. Money will be our undoing. We can watch it happen! History repeats itself so often that we should study it more. We won't. My grandson reports to me that all his American history class was was a study of the civil rights movement and nothing before 1948!?
MorituriMax
1 / 5 (1) Feb 13, 2011
I sincerely hope they can find out how to let someone live to 150, then 1000, then 10000, etc. Always long enough to be around for the next jump.
kaasinees
1 / 5 (4) Feb 13, 2011
If we are really going to live that long, we would need to control our breeding and geneticly enhance ourselves with gene therapy viruses since we can't evolve anymore or to slowly to adept to our environment.

I think it would be a good idea to geneticly enhance people who want to live in space to halt the mass decay cause of no gravity, i volenteer. If i turn into a freak, yay for me.
droid001
not rated yet Feb 13, 2011
Backups of brains is estimated to be available in 2035-45 [Kurzweil et al.]. Once a back up is done then it does not matter when a simulator becomes available in the future.

Backups of brains and living in the simulator is not the same as living young forever (or long enough) in the real world. Anybody wants to try Simulator v1.0 ? Me not. How do I know that's real me?
Sanescience
1 / 5 (3) Feb 14, 2011
Definatelly longer life spans has *GREATLY* improved aspects of our society. Short brutish lives did little for society except promote ability for violence and to make as many babies as possible.

As for needing old experienced people to die to make room for young people, why wait? You should off your parents to get their money, house, and job? F'U. How about living your life like nobody is going to give you nothing so you better get your act together and pull your own weight.

Over population? Please. Western countries with better quality of life and longer life spans are largely slipping into the negative growth category. America is the only positive grown nation, mostly because of immigration. The rest of them have massive challenges ahead of them to not be "washed under" by a human wave of Muslims and Hindus.
Fakeer
not rated yet Feb 14, 2011
Living on Viagra for 230yrs? Hmm I don't know.
dobermanmacleod
2.3 / 5 (3) Feb 14, 2011
The best way (currently) to delay senescence is the CRdiet (i.e. about half the calorie intake). Crsociety.org (this is a non-profit website that sells nothing, but only cites scientific study). By the way, I am on a severe CRdiet and expect to delay senescence three decades!
Beard
not rated yet Feb 14, 2011
The best way (currently) to delay senescence is the CRdiet (i.e. about half the calorie intake). Crsociety.org (this is a non-profit website that sells nothing, but only cites scientific study). By the way, I am on a severe CRdiet and expect to delay senescence three decades!


I'm biased because I'm young still, but I'd rather just keep training at the gym while eating lots of good food to enhance strength, health (but not longevity?) and sexual appeal.

I hope we both make it.
GSwift7
1 / 5 (4) Feb 14, 2011
Mobius:

Wrong on every point


Oh really? I challenge that.

1)It's documented in many studies that younger people tend to have more 'causes' than older people. Those 'causes' can be conservatism or liberalism depending on the cultural climate of the day, but older people tend to become more cynical and less idealistic.

2)Look up average human life expectancy. There are graphs on many sources. It has more than doubled, from 30 to over 70 in a relatively short time.

3)We can see this all around us. There are three US Senators OVER 80 years old, with one at 87 YEARS OLD. There are 18 who are between 70 and 80. That is unprecedented in our history. Top corporate execs and board chairmen follow the same trend.
Sanescience
1 / 5 (3) Feb 14, 2011
1)It's documented in many studies that younger people tend to have more 'causes' than older people. Those 'causes' can be conservatism or liberalism depending on the cultural climate of the day, but older people tend to become more cynical and less idealistic.


What!? Healthy (young) people who have immortality complexes and little patients for how other people feel about things that don't agree with their own views, have more 'causes'? Crazy!

Older people who actually have patients instead of a need for instant gratification? Who do more volunteer work for the benefit of society? Is taking care of children and trying to provide a stable environment for the health of the next generation? Who gather together in community centers and church families? Are the problem?

Your the age version of a raging racist. An ageist. And it is attitudes like yours applied in multiple areas of human society that causes most of the suffering in the world.
TheGhostofOtto1923
3.9 / 5 (19) Feb 14, 2011
Living on Viagra for 230yrs? Hmm I don't know.
If it lasts more than 5 hours you need to see a doctor. Thats what the commercial says.
AdamCC
not rated yet Feb 15, 2011
Regarding immortality, particularly the comments by Moebius ... we are of course taking the discussion way outside the realms of the article BUT: slowing down / reversal of aging is an important part in attaining human immortality (which, as an atheist and an objectivist, is critical to me, because in my selfish world, my life becomes meaningless as soon as I'm gone). However, if that's all there is, immortality will never exist. It would only be a matter of time before you are the victim of some accident or intentional crime. We will also need to strengthen our bodies, probably gradually replacing different pieces with electronic components. Eventually, even our consciousness could be transfered ... I'm not talking in 100 years, I'm talking a very gradual progression, but ultimately allowing us to have virtually indestructible bodies and transferable consciousness - only then will we be immortal.
ScientistAmauterEnthusiast
1 / 5 (1) Feb 16, 2011
Screw living longer in this meat bag, I wanna be made of metal. Just me though, people are more likely to fear me if they are made of flesh still... oh and I want energy weapons...

Oh this mustache? I just really like Charlie Chaplin.. think nothing of it in the polling booth ;)

That's what I fear :]