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Healthy Old Age

Healthy Old Age

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Sirtuins, a family of genes found in everything from yeast to humans, may tell us why we age and how we can live longer, healthier lives. When food runs scarce, these genes, particularly SIR2 in yeast and SIRT1 in mammals, act as our bodies' guardians, beefing up DNA repair and delaying cell death. Recent studies show that mice with activated SIRT1 can even evade (for a while) the diseases associated with aging, including cancer and diabetes, while yeast given a few extra copies of the SIR2 gene will live up to 50 percent longer. Find out how this works in yeast, and what the implications for us might be.—Rima Chaddha


Steps

Asteroid or Comet Impact

 

1. In the beginning

This new, healthy yeast cell has split off from her "mother" and will soon mature to have "daughter" cells of her own. The black element represents the cell's chromosomes.

Did you know?
Under normal conditions, yeast cells only live a few days and produce about 20 offspring. By the time an average yeast cell dies, it will have more than a hundred quintillion descendants (that's one followed by 20 zeroes).




Volcanism

 

2. The daughter

Once her chromosomes replicate themselves, the daughter yeast becomes a mother cell herself (center), dividing to produce her own daughter (underway in upper left). Every daughter cell takes on one copy of her mother's DNA, making the two cells identical.

Did you know?
Some kinds of yeast can mate. Although most yeasts reproduce asexually as shown here, haploid yeast cells, which carry half a yeast's genetic material, will attract each other with pheromones, fuse together to make one cell, exchange genetic information, and have offspring.




Supercontinent

 

3. Separate treatments

To test the effects of SIR2, biologist David Sinclair and colleagues fed one daughter cell (left) a normal diet of glucose while putting the other (right) on a regimen of 30-40 percent fewer calories. This critical decrease in nutrition triggered SIR2's emergency responses, which are designed to preserve the hungry yeast in stressful situations.

Did you know?
Recent scientific findings show that SIR2 can be activated chemically. This means that—with researchers' help—yeast can have their glucose and eat it, too, so to speak, reaping the benefits of calorie restriction without the brutal diet.




Glaciation

Glaciation

 

4. Staying young

  1. As the two yeast cells in this study begin to age and reproduce, the control yeast—the one eating the normal amount of food—begins to show signs of decline. Her DNA loses its structure, becoming loose and combining with itself in ways it shouldn't. Such behavior can cause cancer in humans, but in yeast forces "circles" of repetitive waste DNA—called extrachromosomal rDNA circles, or ERCs for short—to pop out of the chromosomes.

  2. In contrast, the yeast cell with activated SIR2 (invisible inside the chromosome) remains young at this stage. Her DNA retains its structure thanks to the SIR2, thus slowing the formation of waste DNA.

Did you know?
Under normal conditions, healthy yeast can live up to two days. Thus, if one human year equals seven dog years, then one human hour is about four "yeast years."




Bacteria

Bacteria

 

5. Histones

  1. Looking closely at the middle-aged yeast's genetic material, the DNA (the white "spaghetti") is literally coming loose after repeated replication. Chemical tags called acetyl groups that form naturally on the histones (the brown "meatballs") get in the way of the histones' binding tightly to the DNA.

  2. In the yeast cell on the low-calorie diet, SIR2's enzyme clips the acetyl groups off of the histones. This allows the proteins to remain firmly attached to the DNA. With little room to move around, the DNA remains intact, preventing the formation of ERCs and keeping the yeast cell young and healthy.

Did you know?
Thanks to resveratrol, found in red wine and peanuts, and some synthetic molecules, we now know that SIR2 and SIRT1 can be activated chemically. But don't break out the merlot just yet—you would have to drink as many as 1,000 bottles of wine per day to get the amount of resveratrol given to mice in a recent study of Sinclair's.




Methane

Methane

 

6. Staying alive

  1. As the aging mother cell continues to replicate her genome, her copied chromosomes separate to form new, healthy daughter cells. The waste ERCs usually remain inside the mother's nucleus but can occasionally move to the daughter cells, too, causing premature aging in those younger cells.

  2. At this stage, the special histone proteins attracting and condensing the SIR2-activated yeast cell's DNA continue to keep their grip. The hungry mother cell still looks youthful compared to the well-fed control cell.

Did you know?
Yeasts age a lot like we do. Young yeasts are round and smooth, but as they get older, the cells begin to deteriorate. They become slower-moving and wrinkled, even sterile.




Expert

Expert

 

7. Death of a yeast

  1. After about 20 divisions, the control yeast nears the end of her life. The useless ERCs take up so many resources that the mother cell can no longer replicate her own genome and will die.

  2. The SIR2-activated yeast shows only minor signs of aging at this point, if any at all. She will continue to thrive for 10 or more divisions, soon forming ERCs that will lead to her own demise.

Did you know?
Yeast cells get bigger as they age, holding more than 1,000 waste ERCs as they near death. That is more DNA than exists in any yeast cell's actual genome.




Expert

 

The human factor:
What all this means for us


"When we started working on yeast aging 20 years ago, we were laughed at by most," says David Sinclair, an associate professor of pathology and researcher of aging at Harvard Medical School. "But today we now know that there are certain genes that control lifespan (called 'longevity genes') and that these genes could change the course of medical research as we know it. We appear to be on the verge of understanding if and how these genes affect aging and age-related diseases in humans. If it is true that longevity genes control human health and lifespan, we might be able to make drugs that activate these ancient pathways and use them to treat diseases of aging, such as cancer, heart disease, diabetes, and even Alzheimer's disease. Such drugs might one day allow us to live healthy, productive lives into our 90s and beyond."





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