Mammals have approximately the same genes. Yet from skittering lab mice to magnificent bowhead whales or the elegant elephant, the difference in lifespan can be more than a century. Why?

An international consortium is decoding the mystery. Rather than comparing different genetic letters between species, they turned the focus to gene expression—that is, how genes are turned on or off. Known as epigenetics, the field has gained steam as a biological clock to gauge health, aging, and even predict how long a species can live.

The tour-de-force study, published last week in Science, covered nearly 15,500 samples from 348 mammalian species both small and large. The entire animal register looks like the population of an international zoo. On one end are the little guys: mice, bunnies, cats, and dogs. One the other are the prowlers and mammoths of our world: panthers, cheetahs, bottlenose dolphins, and elephants. Sprinkled within the lineup are the rather bizarre: the vampire bat, Tasmanian devil, and Somali wild ass. And yes, humans do make an appearance, along with other non-human primates.

There’s a reason for analyzing the animal kingdom in all its glorious diversity. By studying mammals using the same biological clock and comparing each profile, we can begin to parse genomic “hot spots” that govern aging and lifespan, in turn homing in on methods to regulate those spots and delay or even reverse the aging process.

“We’ve discovered that the life spans of mammals are closely associated with chemical modifications of the DNA molecule, specifically known as epigenetics,” said Dr. Steve Horvath at the University of California, Los Angeles (UCLA), who led the study.

Aging aside, the computational tools developed can also help scientists link epigenetics to other complex traits, such as height, weight, metabolic disorders like Type 2 diabetes, or neurological troubles.

To Dr. Alex de Mendoza at the Queen Mary University of London, who was not involved in the project, the takeaway is that we now have a universal marker to assess aging and other traits across mammals. “Therefore, experimental treatments aimed at modifying aging…can now be tested” in a wide variety of animals across the evolutionary scale with a standard “ruler” for epigenetic aging, he wrote.

The Trouble With Age

The number of candles on your birthday cake doesn’t always reflect your biological age.

We all know people who—thanks to genetics or lifestyle—look and behave much younger than their chronological age. Scientists have long known that it’s not just anecdotal: these people show less signs of aging in their metabolism, stem cells, inflammation, and DNA expression.

Roughly a decade ago, Horvath wondered if it’s possible to use these aging markers to gauge a person’s biological age irrespective of how many years they’ve been on Earth. He honed in on one epigenetic marker: DNA methylation.

Most of our cells carry the same genetic blueprint. What differentiates neurons from heart cells from muscle cells is how the genes are expressed. DNA methylation is a powerful way to control when and where genes are shut off. The process adds a small chemical that physically blocks the DNA expression machinery from accessing genes, in turn inhibiting them from being translated into proteins. Each cell type, tissue, and organ has a unique DNA methylation fingerprint, which steadily shifts with age.

Horvath’s pioneering work developed a predictor of biological age in multiple tissues using DNA methylation alone from 8,000 samples. Since then, his—and others’—work spurred multiple epigenetic clocks that also predict age-related diseases, such as cancer, brain health, or heart problems.

“DNA methylation is easier to measure than other classic gene regulatory mechanisms,” explained Mendoza.

Yet the sole focus on humans seemed too narrow. Evolution crafted genetic changes across species to help each adopt to their unique environments. Can it also shape epigenetic landscapes?

A Universal Clock

The team recently expanded their DNA methylation clock to over 200 different mammalian species. It’s a tough problem: they first had to hunt down DNA methylation sites on genetic material conserved across different species. They then manufactured tiny “probes” that detect DNA methylation and can tolerate small mutations across species.

The resulting chip, called the Horvath Mammalian Array, detected epigenetic clocks in multiple tissue types such as blood, skin, liver, kidney, brain, and more in different species. The chip is a meticulously curated multi-arrayed probe for a subset of DNA methylation sites, which makes it easier to study how DNA methylation associates with traits like lifespan without the need for large sample sizes. At a fraction of the cost of previous methods, the chip directly compares DNA methylation sites across tissue samples and species.

An Evolutionary Epigenetic Clock

The new study further expands the work to 348 species and 15,456 samples, with up to 70 tissues per species. The hefty collaboration spanned from academic institutions to the Smithsonian and Sea World.

The team first honed in on highly conserved DNA methylation sites in each species. The results painted an epigenetic evolutionary tree—dubbed “phyloepigenetic tree”—that surprisingly recapitulated the mammalian tree of life.

“Our results demonstrate that DNA methylation is subjected to evolutionary pressures and selection,” said the authors.

Using a machine learning model, the team then nailed down 55 different DNA methylation modules (each endearingly dubbed with a color shade) associated with a complex trait. Some module colors were able to detect the organ or sex of the sample regardless of the species.

More intriguing were a handful of DNA methylation spots linked to lifespan. Several sites directly controlled powerful genes involved in rejuvenation. Two in particular stood out: OCT4 and SOX2, both better known for being key Yamanaka factors. These genes help revert mature cells—for example, skin cells—to an embryonic stage, wiping their identity and allowing them to start anew. When the team dosed mice with these factors, the DNA methylation clock turned back in their skin and kidneys.

“Therefore, regulation of these factors across the life of mammals might drive different life spans, with some species expressing them for longer,” said Mendoza.

Another analysis found several DNA methylation sites linked to maximum lifespan. These are stubborn but reliable clocks that don’t change with age. Most are presumably “established at birth,” said the team.

Tick Tock Goes the Clock

Although comprehensive, the study is hardly the last word on DNA methylation clocks.

There are plenty of outcasts. Body weight usually correlates with longevity. Yet some small dog breeds are biologically younger than comparative larger ones. Some bats can live more than three decades—far longer than predicted based on their body weight alone. The epigenetic platform could be a starting point for analyzing their unique genetic fingerprints.

More broadly, the clocks are unveiling not just how we age, but why. In a sister article, Horvath’s team found specific DNA letters with methylation that change with age across multiple species. The sites were near genes that control processes from birth to death, including those involved in development and cancer.

Their conclusion? “Aging is evolutionarily conserved and intertwined with developmental processes across all mammals,” they said.

That’s not to say we’re helpless in slowing the ravages of time. For example, the universal epigenetic clock could bridge anti-aging therapies in lab mice and be extrapolated to humans. Therapies range from behavioral interventions—cutting down calories and exercising—to drugs that kill off toxic “zombie cells,” or those that target epigenetic processes. Horvath and others are readily collaborating with Altos Labs, a startup for cellular rejuvenation therapies backed by Jeff Bezos and others.

With a universal DNA-based marker, said Mendoza, we can test these therapies on other mammalian species, each with their unique epigenetic and metabolic makeup.

Image Credit: GPA Photo Archive

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• Source: https://singularityhub.com/2023/08/15/scientists-studied-348-mammals-to-discover-why-some-live-for-months-while-others-last-centuries/