Scientists decipher mechanisms in cells for extending human longevity

A sirtuin-dependent intermittent pattern of chromatin silencing during yeast aging that is crucial for longevity
November 6, 2017

Aging cells periodically switch their chromatin state. The image illustrates the “on” and “off” patterns in individual cells. (credit: UC San Diego)

A team of scientists at the University of California San Diego led by biologist Nan Hao have combined engineering, computer science, and biology technologies to decode the molecular processes in cells that influence aging.

Protecting DNA from damage

As cells age, damage in their DNA accumulates over time, leading to decay in normal functioning — eventually resulting in death. But a natural biochemical process known as “chromatin silencing” helps protect DNA from damage by converting specific regions of DNA from a loose, open state into a closed one, thus shielding DNA regions. (Chromatin is a complex of macromolecules found in cells, consisting of DNA, protein, and RNA.)

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 (such as resveratrol and more recently, NMN, as discussed on KurzweilAI) to aid chromatin silencing in the hopes of slowing the aging process.

To silence or not to silence? It’s all about the dynamics.

However, scientists have also found that such chromatin silencing also stops the protected DNA regions from expressing RNAs and proteins that carry out biological functions, so excessive silencing could derail normal cell physiology.

To learn more, the UC San Diego scientists turned to cutting-edge computational and experimental approaches in yeast, as described in an open-access study published in Proceedings of the National Academy of Sciences. That allowed the researchers to track chromatin silencing in unprecedented detail through generations during aging.

Here’s the puzzle: They found that a complete loss of silencing leads to cell aging and death. But continuous chromatin silencing also leads cells to a shortened lifespan, they found. OK, so is chromatin 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.”

What about nutraceuticals?

So are nutraceuticals to aid chromatin silencing still advised? According to a statement provided to KurzweilAI, “since the study focused on yeast aging, much more investigation is needed to inform any questions about chromatin silencing and nutraceuticals for human benefit, which is a much more complex issue requiring more intricate studies.”

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

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

The research was supported by the National Science Foundation, University of California Cancer Research Coordinating Committee (L.P.); Department of Defense, Air Force Office of Scientific Research, National Defense Science and Engineering; Human Frontier Science Program; and the San Diego Center for Systems Biology National Institutes of Health.

Nan Hao | This time-lapse movie tracks the replicative aging of individual yeast cells throughout their entire life spans.

Nan Hao | periodic switching during aging

Abstract of Multigenerational silencing dynamics control cell aging

Cellular aging plays an important role in many diseases, such as cancers, metabolic syndromes, and neurodegenerative disorders. There has been steady progress in identifying aging-related factors such as reactive oxygen species and genomic instability, yet an emerging challenge is to reconcile the contributions of these factors with the fact that genetically identical cells can age at significantly different rates. Such complexity requires single-cell analyses designed to unravel the interplay of aging dynamics and cell-to-cell variability. Here we use microfluidic technologies to track the replicative aging of single yeast cells and reveal that the temporal patterns of heterochromatin silencing loss regulate cellular life span. We found that cells show sporadic waves of silencing loss in the heterochromatic ribosomal DNA during the early phases of aging, followed by sustained loss of silencing preceding cell death. Isogenic cells have different lengths of the early intermittent silencing phase that largely determine their final life spans. Combining computational modeling and experimental approaches, we found that the intermittent silencing dynamics is important for longevity and is dependent on the conserved Sir2 deacetylase, whereas either sustained silencing or sustained loss of silencing shortens life span. These findings reveal that the temporal patterns of a key molecular process can directly influence cellular aging, and thus could provide guidance for the design of temporally controlled strategies to extend life span.