Pocket watch with face of a woman at different ages where the numbers would be, on a DNA chain.

Different organisms and cells change over time, making it difficult to measure biological aging. Alterations in the epigenetic markers on DNA can be looked at by new computationalclocks.

Myriam Wares is featured in a magazine.

Steve Horvath was looking for the pangolin. He said he wanted them because he didn't have an order.

Horvath, who used to be an anti-aging researcher at the University of California, Los Angeles, has been writing to zoos, museums, aquariums and laboratories for as long as 10 hours a day. He's met the keepers of the bats and devils. He's reached out to the farthest corners of the world, asking for the genetic material of flying foxes, vervet monkeys, minipigs and bowhead whales.

He has built a computational clock that can calculate the age of animals as diverse as shrews, koalas, zebras, pigs and whales, just by looking at their genes. Horvath was working on a project that would measure the biological age of any mammal.

The nearest clock or calendar seems to be easier to use to measure age. Some people show the effects of age more quickly than others. Scientists have been searching for a way to measure biological aging for decades. Horvath is a principal investigator at Altos Labs, a startup working toward the rejuvenation of cells.

The pan-mammalian clock was finished by Horvath and his colleagues. He and others are trying to identify the processes that make a clock possible. Horvath believes that understanding why clocks like this one work could lead to the root cause of aging.

Ground pangolin walking through a reserve in South Africa.

A pan-mammalian epigenetic aging clock has been created by sampling more than 300 animals, including the pangolin. Some pangolins may live a long time.

His clock is based on analyses of the chemical tags that hang on DNA like charms on a bracelet. Epigenetics is the field that studies heritable information that isn't in the genetic code. A dozen years ago, Horvath and his colleagues began applying their know-how to building the clock, first to assess the age of DNA from saliva, and later to determine the age of blood, liver and other individual tissues.

Many biologists were skeptical because the clock was based on statistics. The accuracy of the clock was tested and it stood up. The Horvath clock was used by scientists to measure the aging of cells because it was better at determining the state of the body and the risk of disease than chronological age. Vadim Gladyshev said that Epigenetic clocks are closer to the process of aging than any other markers. Scientists are rethinking their ideas about aging and diseases because of the clock.

Sara Hgg said that she is starting to think about whether advanced biological aging is useful in breast cancer research. She said that if the clock could illuminate how to stop the aging process, we could prevent many diseases.

Seeing a Signal

The clock for aging was thought to be within reach many times. In the early 1960s, they discovered that cells grow in culture but die after 40 to 60 rounds of replication, suggesting that cells have an aging clock. Researchers thought they might have found the clock's mechanism when they isolated the ends of chromosomes that shorten when a cell divides.

The aging clock didn't work out with the telomeres. Humans and some other species don't have a correlation between age and mortality. Telomere doesn't really track age. Ken Raj is a principal investigator at Altos labs.

Stained condensed chromosomes against a black background, with red spots indicating the locations of telomeres at their ends.

Horvath started working on a clock based on theRNA transcripts of a cell's active genes in 2009, as an alternative to telomere length. The approach didn't work for the next two years.

Horvath helped out a colleague at UCLA. The researcher wanted to know if there was a connection between sexual orientation and epigenetics by collecting saliva from identical twins who were different in sexual orientation. Horvath's twin brother is gay. They provided their spit.

The study looked at where the cytosine bases are located and checked which of them were altered. The only bases that the groups attach to are cytosines The lab-on-a chip technology made it possible to test tens of thousands of sites in a single cell. Horvath volunteered to be a statistician for the colleague.

Anti-aging researcher Steve Horvath in his laboratory at the University of California, Los Angeles.

They were looking for something, but he didn't find it. Horvath said there was no signal for homosexual activity. Since the ages of the twins in the study spanned decades, I asked if I could look at aging effects.

Horvath had shied away from using epigenetic data in his own research. It had seemed unlikely to show a connection between aging and the relationship of methylation patterns to genes. There was no need to look now that he had this data.

The age of the twins was matched by Horvath. Not all the cells in a sample will show the same pattern. It is possible to measure the proportion of cells that are methylated. In one sample, 40% of cells may be methylated at a certain position; in another, that proportion may be 45% or more.

The accuracy was boosted by looking at more places.

He said that this changed everything for him. The signal for aging blew me away.

Horvath used a saliva sample to build a model that predicted a person's age based on their epigenetic status. He said that they could measure your age by spitting in a cup.

He was creating epigenetic clock models to evaluate the biological ages of various tissues. He measured the proportions of cells in each sample to see if they were different from one another. He used the data to create profiles of the tissues that described the proportions of cells.

He fed a computer thousands of epigenetic profiles to build a clock. The computer used machine learning to link ages. The number of prediction sites was narrowed. Horvath tested the best formula for age on a separate set of samples of known ages and found it to be the most accurate.

He published a formula for a "pan-tissue" clock in 2013). Daniel Belsky said that the pan-tissue clock was the game-changer. The formula was applied to every human cell. Horvath made the software available on the internet. Biologists can find out how much time has been spent on cells by uploading their own data.

Quantifying Decline

Horvath's pan-tissue clock accurately predicted chronological age. The differences between chronological and biological age were reflected in it. When the epigenetic clock estimated someone's age was more than their chronological age, they faced a higher risk of diseases and death. The risk went down when the clock estimated the age of the person. The epigenetic clock was derived from chronological age data.

Naked mole rat eating amid the litter of its cage floor.

The epigenetic level of naked mole rats is much slower than that of mice.

Horvath wanted to track biological age. He and his colleagues, including Morgan Levine (a pathology researcher at Yale University who recently joined Altos Labs) and Luigi Ferrucci of the National Institute on Aging, trained an algorithm on a measure that included chronological age as well as the results of nine blood chemistry tests. The data came from the blood of thousands of people. Overall mortality and the risk of cardiovascular disease, lung disease, cancer and diabetes were predicted by the clock. A year later, Horvath and a team led by Ake T. Lu of UCLA released Grim Age, which looked at a person's sex, chronological age, smoking history and blood-protein mortality markers.

Belsky and his colleagues introduced a tool in 2020 that acts as an aging speedometer. They quantified the rate of change in 19 markers of organ function at four years old, compiled them into a single index, and modeled it using methylation. Belsky said that they are quantifying the process of age related decline and system integrity. He said that those who age faster by this measure die younger and that it predicts mortality as well as Grim Age.

Age-Old Question

Horvath was approached by representatives of the Allen Family Foundation. He was told to dream big because the foundation supports high risk endeavors. They told us to find a project that nobody else would fund.

Horvath suggested an aging clock for all animals. As Horvath realized the magnitude of what it would involve, the proposal became a clock for all mammals.

Horvath had data from 128 mammals by January 2021. The same formula is used for a mouse or a rat or a dog. Horvath said that they can measure aging in all of them. He was still looking for more.

Horvath was in contact with a pangolin expert in Zimbabwe who offered him supplies to collect data. They didn't know how long pangolins lived. Some accounts said it would take 15 to 20 years. He wrote that the animal that they aged recently was 34 years old.

The process of aging is closer to the Epigenetic clock.

Vadim Gladyshev is a medical student.

Horvath built a pangolin clock from the tissue data he received. I have a pig clock that you can get. Horvath has a clock for animals. Scientists in the field benefited from each clock. The elephant researchers wanted the elephant clock to be used to determine the age of wild populations.

A clock that combines all of them can answer a question about aging. One view is that your body is just like your shoes. The pan-mammalian clock's success suggests that something causes cells to fail on a certain timetable, possibly because of genes that don't switch off when their work is done. Raj is one of the clock's more than 100 builders.

The data shows that aging begins very early. Gladyshev and his colleagues describe a clock that shows the stages of development of mammals. They discovered that a rejuvenation of sorts reduces the embryo's age to zero. Even though human children are growing stronger, not weaker, during this time, mortality in humans declines until about 9 years old. Raj said that it nails the question of aging down to a process that is inextricable from development.

Even though the naked mole rat's chances of dying do not increase with chronological age, two recent studies show that it ages epigenetically. Gladyshev believes that mortality rate is not the best measure of aging. Being alive is the cause of aging.

The effects of experience, behavior and the environment are reflected in aging. Smoking and sun exposure can speed it up, as measured by methylation and other markers, while exercise or a low- calories diet can stall it. A paper published last week showed that the same is true for bats when it comes to aging. In a colony of monkeys on an island off the coast of Puerto Rico, a clock suggests that Hurricane Maria accelerated the aging process.

Original Sin

Some people don't know why the clock works. Researchers are still learning how genes and pathways affect the health of cells, tissues and organs, even though some genes and pathways have been identified. Horvath called it the original sin of the construction. It is based on astatistical regression model that is compatible with biology.

A cluster of hibernating bats hang together from the ceiling of a cave.

Bats age much more slowly when they are in the deep torpor known as hibernation.

Raj and Horvath want to atone for their sins. Perturbations of the biochemical pathways the body uses to sense its need for vitamins and minerals have been found to be related to the effects of diet on aging. It gets faster when the workings of mitochondria are stopped. Stem cells are tracked by the clock The authors wrote that if these processes are connected at a deeper level, epigenetic clocks could reveal unifying mechanisms for aging.

It's not clear what unifying mechanisms might be or why methylation status tracks aging so well. Hgg doesn't know if epigenetic clocks are linked with aging.

Matt Kaeberlein is a researcher at the University of Washington School of Medicine in Seattle who studies the biology of aging. He said that it was not clear whether they were measuring more than one dimensions of biological age. There is a problem with conflating epigenetic age with biological age. I don't think those are equivalent in my opinion.

Raj thinks that the changes to the genes reflect a loss of cellular identity. The pattern of gene expression in a heart cell is different from the pattern of genes in a liver cell. Raj suggests that some of the controls may be lost, replaced by re-emerging programs that should be turned off.

Some studies suggest that there is room for improvement when it comes to biological age. A more precise predictor could combine quantifiable cellular properties with an index of frailness. Hgg said that they can measure a lot of things in a human being. The more you measure, the more accurate you will be.

Hgg warned about the limited uses of the melatonin clock. People can buy a readout of their biological age from various commercial sources, but not only are the results often inconsistent, they lack clinical relevance because the clocks were meant for group level analyses in research. She said that they are not built to be predictors.

Will someone have a longer life if they change their lifestyles in a way that lowers their biological age? Kaeberlein didn't know that yet.

Horvath is working on a paper about his clock. The gaps in his collection still bother him even though he seems to have reached his goal. In May, he sent an email to senior curators at a museum in Australia about getting tissue from a small blind creature. He said they would like to add more data from more mammals.

Horvath set out to analyze 30 species, but 30 became 50, then 100, then more than three times that. He said that he needed to pace himself because of his desire to collect more.