Scientists decipher mechanisms underlying the biology of aging

November 2, 2017
Aging cells periodically switch their chromatin state. The image illustrates the "on" and "off" patterns in individual cells. Credit: UC San Diego

Understanding the factors that control aging has been one of humanity's endless pursuits, from the mystical fountain of youth to practical healthful regimens to prolong life expectancy.

A team of scientists at the University of California San Diego has helped decipher the dynamics that control how our cells age, and with it implications for extending human longevity. As described in a study published in the Proceedings of the National Academy of Sciences, a group led by biologist Nan Hao employed a combination of technologies in engineering, computer science and biology to analyze molecular processes that influence aging.

As cells age, damage in their DNA accumulates over time, leading to decay in normal functioning and eventually resulting in death. A natural biochemical process known as "chromatin silencing" helps protect DNA from damage. The silencing process converts specific regions of DNA from a loose, open state into a closed one, thus shielding DNA regions. Among the molecules that promote silencing is a family of proteins—broadly conserved from bacteria to humans—known as sirtuins. In recent years, chemical activators of sirtuins have received much attention and are being marketed as nutraceuticals to aid chromatin silencing in the hopes of slowing the aging process.

Yet at the same time, scientists have found that such chromatin silencing also stops the protected DNA regions from expressing RNAs and proteins that carry out biological functions, and as a result, excessive silencing could derail normal cell physiology.

Single yeast cells aging in a new microfluidic chip. The aging mother cells are trapped at the bottom of finger-shaped chambers, producing daughter cells until their final death. Credit: UC San Diego

Using cutting-edge computational and experimental approaches in yeast, which allowed the researchers to track chromatin silencing in unprecedented detail through generations during aging, the UC San Diego scientists discovered that a complete loss of such silencing leads to accelerated cell aging and death. However, the researchers similarly found that continuous chromatin silencing also leads cells to a shortened lifespan.

So is silencing or not silencing the answer to delay aging? The answer derived from the new study: Both.

According to the researchers, nature has developed a clever way to solve this dilemma.

"Instead of staying in the silencing or silencing loss state, cells switch their DNA between the open (silencing loss) and closed (silencing) states periodically during aging," said Hao. "In this way, cells can avoid a prolonged duration in either state, which is detrimental, and maintain a time-based balance important for their function and longevity."

Cells periodically switch between "on" and "off" in their chromatin state during aging. Aged cells lose this switching capability, resulting in cell death. These findings uncover a potential cause of cellular aging and suggest new ways to promote longevity. Credit: UC San Diego

Because they conducted their experiments in yeast, the researchers say analyzing such dynamics in humans is likely to be much more complex and require more intricate studies.

"When cells grow old, they lose their ability to maintain this periodic switching, resulting in aged phenotypes and eventually death," said Hao. "The implication here is that if we can somehow help to reinforce switching, especially as they age, we can slow their aging. And this possibility is what we are currently pursuing."

Hao credits the findings to a multidisciplinary team of UC San Diego researchers who have complementary expertise and share a common interest in the study of aging, including faculty, students and postdoctoral fellows. In addition to Hao's expertise in Molecular Biology/Quantitative Biology, other faculty members in the team include Lorraine Pillus (Molecular Biology), Jeff Hasty (Molecular Biology/Bioengineering) and Lev Tsimring (BioCircuits Institute). The PNAS paper marks the first significant findings from the collaboration.

"I believe this collaboration will produce in the near future many new insights that will transform our understanding in the basic of aging and will lead to new strategies to promote longevity in humans," said Hao.

Explore further: Key factor identified in gene silencing

More information: Yang Li et al. Multigenerational silencing dynamics control cell aging, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1703379114

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derphys
not rated yet Nov 02, 2017
"As cells age, damage in their DNA accumulates over time" is also true for life over many generations, and logically over 4 billons years life should be supressed by too much DNA damages, even with sex. The errors correction must be perfect in life over many billions generations in order to have living organisms and not all dead..
nanotech_republika_pl
not rated yet Nov 02, 2017
"As cells age, damage in their DNA accumulates over time, leading to decay in normal functioning and eventually resulting in death." This implies that the DNA mutations grow fast during the lifetime and these mutations are much higher in old age (as shown by increased incidence of mutations and therefore cancer).

The problem with this idea might be that the accumulation of random mutations in DNA is not progressing as fast as it is suggested here, nothing near the exponential growth of a chance of cancer. This is shown in this graph in another paper
https://www.ncbi....gure/F1/

The graph shows very quick increase of mutations up to the time of maturity and then virtually a flat line. If this is true, why would cancer/muations occur not as frequent in early adulthood as they do in an aged body?!

nanotech_republika_pl
not rated yet Nov 02, 2017
... Maybe be the mutations in DNA are not the main cause of the shift in the epigenetic pattern? Maybe damage to other parts of the cell are the main cause of ageing? SENS.org has interesting ideas about that.
MLW
not rated yet Nov 03, 2017
"As cells age, damage in their DNA accumulates over time" is also true for life over many generations, and logically over 4 billons years life should be supressed by too much DNA damages, even with sex. The errors correction must be perfect in life over many billions generations in order to have living organisms and not all dead..


This is postulated as a driving force behind rising complexity. Mutations are not only a source of detrimental damage, but also adaptations. Damage control mechanisms evolve to combat detrimental mutations, but they are susceptible to mutation themselves. Natural selection and the evolution of multi-level error correction was/is the answer. It's a strategy for most organisms to produce far more offspring than can reasonably be expected to survive. Large, complex organisms tend to have more sophisticated error correction mechanisms.
xponen
5 / 5 (1) Nov 03, 2017
They figured it all out, I think the cell's sleep cycle is the most important tool to prolonging cell's lifespan, it is the same concept used by engineers to promote energy saving & increasing Mean Time Before Failure (MTBF) of electronic equipment (such as CPUs) since these hardware began to degrade by mere heat and electricity and is too complex to service once assembled.

It explain why eating less literally increase your lifespan because it promote energy conservation hence it promote cell's sleep.
Whydening Gyre
not rated yet Nov 03, 2017
They figured it all out, I think the cell's sleep cycle is the most important tool to prolonging cell's lifespan, it is the same concept used by engineers to promote energy saving & increasing Mean Time Before Failure (MTBF) of electronic equipment (such as CPUs) since these hardware began to degrade by mere heat and electricity and is too complex to service once assembled.

It explain why eating less literally increase your lifespan because it promote energy conservation hence it promote cell's sleep.

I get more naps than anybody I know...
torbjorn_b_g_larsson
not rated yet Nov 04, 2017
Interesting application of micromechanics and fluorescence techniques.

@derphys: "The errors correction must be perfect in life over many billions generations in order to have living organisms".

Well, no, that would obviously not work. And we see that in fact baseline evolution is near neutral drift (c.f. Wikipedia), where most genes seems to be slightly deleterious (non-perfect and harmful) which explains why molecular clocks correlates with geological time rather than biological (generational).

@MWL: Selection is a mechanism of the process of evolution rather than an evolved response to damage. It is based on the exponential increase capability of cells and heritable differential reproduction.

@xponen: The main problem with dragging in circadian rhythms, which may not exist in all cells, is that these experiments happened over 0.5 - 1.5 days. Yeast cells age quickly!
torbjorn_b_g_larsson
not rated yet Nov 04, 2017
@nanotech: You are looking at tissues, whole complex multicellular organisms and cancer diseases of the latter, which this study cannot feasibly explain all of. I frankly see no problem with their reference claim that "Cellular aging is generally driven by the accumulation of genetic and cellular damage (1, 2)" and then the result that "intermittent silencing dynamics is important for longevity".

By the way, speaking of the aging, hopeful but still unsupported, ideas of de Grey [is it SENS now!?], the paper notes that the result can "provide guidance for the design of temporally controlled strategies to extend life span."

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