Aging – BIOLOGY, ENVIRONMENT & MORE

WOO-HOO!! WE CAN NOW REVERSE CELL AGING!

Turning off a newly identified enzyme could reverse a natural aging process in cells.

Research findings by a KAIST team provide insight into the complex mechanism of cellular senescence and present a potential therapeutic strategy for reducing age-related diseases associated with the accumulation of senescent cells.

Simulations that model molecular interactions have identified an enzyme that could be targeted to reverse a natural aging process called cellular senescence. The findings were validated with laboratory experiments on skin cells and skin equivalent tissues, and published in the Proceedings of the National Academy of Sciences (PNAS).

“Our research opens the door for a new generation that perceives aging as a reversible biological phenomenon,” says Professor Kwang-Hyun Cho of the Department of Bio and Brain engineering at the Korea Advanced Institute of Science and Technology (KAIST), who led the research with colleagues from KAIST and Amorepacific Corporation in Korea.

Cells respond to a variety of factors, such as oxidative stress, DNA damage, and shortening of the telomeres capping the ends of chromosomes, by entering a stable and persistent exit from the cell cycle. This process, called cellular senescence, is important, as it prevents damaged cells from proliferating and turning into cancer cells. But it is also a natural process that contributes to aging and age-related diseases. Recent research has shown that cellular senescence can be reversed. But the laboratory approaches used thus far also impair tissue regeneration or have the potential to trigger malignant transformations.

Professor Cho and his colleagues used an innovative strategy to identify molecules that could be targeted for reversing cellular senescence. The team pooled together information from the literature and databases about the molecular processes involved in cellular senescence. To this, they added results from their own research on the molecular processes involved in the proliferation, quiescence (a non-dividing cell that can re-enter the cell cycle) and senescence of skin fibroblasts, a cell type well known for repairing wounds. Using algorithms, they developed a model that simulates the interactions between these molecules. Their analyses allowed them to predict which molecules could be targeted to reverse cell senescence.

They then investigated one of the molecules, an enzyme called PDK1, in incubated senescent skin fibroblasts and three-dimensional skin equivalent tissue models. They found that blocking PDK1 led to the inhibition of two downstream signaling molecules, which in turn restored the cells’ ability to enter back into the cell cycle. Notably, the cells retained their capacity to regenerate wounded skin without proliferating in a way that could lead to malignant transformation.

The scientists recommend investigations are next done in organs and organisms to determine the full effect of PDK1 inhibition. Since the gene that codes for PDK1 is overexpressed in some cancers, the scientists expect that inhibiting it will have both anti-aging and anti-cancer effects.

THE SCIENTISTS CONDUCTED WHAT IS KNOWN AS AN ENSEMBLE MODEL SIMULATION TO IDENTIFY MOLECULES THAT COULD BE TARGETED TO REVERSE CELL SENESCENCE. THEY THEN USED THE MODEL TO PREDICT THE EFFECTS OF INHIBITING PDK1 IN SENESCENT CELLS, AND CONFIRMED THE RESULTS IN LAB-CULTURED CELLS AND SKIN EQUIVALENT TISSUE MODELS.

“THE KILLER MUTATIONS”

Scientists have discovered a handful of ultrarare mutations present in our cells from birth that likely shave years off a person’s life. Each of these DNA variants, most likely inherited from our parents, can reduce life span by as much as 6 months, the researchers estimate. And different combinations can dictate how long people live before developing age-related diseases such as cancer, diabetes, and dementia.

A person’s genes don’t set a specific natural life span—diet and many other factors play large roles, too—but studies have shown that DNA variants can influence the aging process. Biologists chalk up less than one-third of that influence to the genes we inherit. The source of other age-influencing DNA variation is environmental: Sun damage, chemical exposure, and other insults that create thousands of random mutations. Each cell’s collection of these environmental mutations differs, and most don’t greatly impact a person’s life span.

Hunting for these rare mutations, which are found in less than one in every 10,000 people, required a group effort. Harvard University geneticist Vadim Gladyshev, a senior co-author in the new study, partnered with academic colleagues and a biotech company called Gero LLC to scour the UK Biobank, a public database containing the genotypes of about 500,000 volunteers.

Using more than 40,000 of these genotypes, the team looked for correlations between small changes in DNA and health conditions, a so-called genomewide association study. Specifically, the variants they were targeting knock out genes entirely, depriving all the cells in the body of certain proteins.

On average, each person is born with six ultrarare variants that can decrease life span and “health span,” the amount of time people live before developing serious diseases, the team reports this month in eLife. The more mutations, the more likely a person was to develop an age-related illness at a younger age or die. “The exact combination matters,” Gladyshev says, but in general, each mutation decreases life span by 6 months and health span by 2 months.

The results build on what is already known about aging: “Family genes” matter. But rather than studying the common mutations found in especially long-lived people, researchers can now target rarer variants present in everyone. Gladyshev hopes this information can be used in clinical trials to categorize participants by their mutations in addition to things like gender and actual age.

He admits the findings are potentially controversial, as they minimize the perceived contribution to

aging of environmental “somatic” mutations acquired throughout life. Somatic mutations “live in a larger universe of age-related changes” influenced by lifestyle, he says, adding that changes to hormone and gene expression also come with age. “They [all] contribute to the aging process, but on their own they do not cause it.”

Jan Vijg, a geneticist at the Albert Einstein College of Medicine who studies the role of somatic mutations in aging, agrees, though he adds that somatic mutations can still cause diseases such as skin cancer that decrease life span.

Alexis Battle, a biomedical engineer at the Johns Hopkins University School of Medicine, points to an important caveat, however: The new research only looked at the “exome,” the 1% of the genome that actively builds the proteins that direct our cells. The rest is largely a black box, although growing evidence shows it can affect gene expression. Both Battle and Vijg agree that this DNA could be even more important in aging than the regions targeted by Gladyshev and his colleagues.

Going forward, Gladyshev would like to repeat his analysis on DNA from centenarians: those that live to be older than 100. “Most of the previous research focused on what these people have that makes them long-lived,” he says. “But [we want to look at] the opposite—it’s what they don’t have.”

Illustration of a damaged ribonucleic acid or dna strand