Please forgive Juan Ponce de Leon, but the secrets to human immortality don’t reside in Florida. He should have traveled west to Southern California, near present day Loma Linda, or south to the Nicoya Peninsula of Costa Rica. Or, instead of crossing the Atlantic altogether, he could have set sail to the more familiar Mediterranean islands of Sardinia or Icaria, much closer to his birth country Spain. If he was feeling particularly adventurous, he may have continued along the Silk Road through China, across the East China Sea, to touch the beaches of Okinawa.

Loma Linda. Nicoya. Sardinia. Icaria. Okinawa.

These five places are “Blue Zones,” where people tend to live longer than the rest of us. Scientists who hypothesize that the real Fountain of Youth will be found buried within our genomes, or synthesized in a test tube in the laboratory, have flocked to these locations to study the people living there to find new clues to human longevity. They’ve found that females in Blue Zones are more likely to enjoy centenarian status (living beyond 100) and worldwide there are more than four times as many female centenarians than males. Curiously, this ratio is closer to one to one in Sardinia, where it’s believed a mixture of social support networks within the island communities promote psychological well-being that may interact with genetic factors.

Blue Zones are studied to further understand why one individual instead of another can become a centenarian (or in some cases, reach supercentenarian status, those few individuals, estimated at just a couple hundred to have lived during the course of human history, to reach beyond 110 years.) It’s clear the answer lies mired within a mixture of our own genetic predisposition and our environmental exposures—the battle between nature and nurture. But in order to slow or stop aging, we must first comprehend what exactly is aging. Armed with that knowledge, it’ll be easier to intervene and possibly prevent our own mortality.

The Wide World of Aging

Aging is a time-dependent, functional decline in physiological integrity that impairs almost all living organisms and increases one’s susceptibility to death. The scale of how organisms age are vastly different. The life span of an insect generally occurs between a few days to a few weeks, but some insects like the termite queen can live for decades. Animals range from months and a handful of years to the impressive duration of the Galapagos tortoise (~150 years), bowhead whale (~200 years), all the way to the whale shark, with some documented to be over 500 years. Humans have a long way to go. The oldest documented person was Frenchwoman Jeanne Calment, who lived 122 years and 164 days and passed away in 1997. She was born when General Ulysses S. Grant was President of the United States. Currently, Kane Tanaka of Japan is the oldest confirmed person alive. She is over 115 years and 332 days and Teddy Roosevelt was wandering the halls of the White House when she was born.

But if the whale shark impressed you, we haven’t even touched the true champions of longevity, who reside within the plant kingdom. The oldest known individual plant is a Great Bristlecone Pine dated to over 5,000 years older than the Great Pyramid of Giza. A creosote bush in the Mojave Desert, called King Clone, is estimated to be over 11,000 years old. King Clone is a clonal colony, meaning the plant has asexually produced individual offspring that are genetically identical and connected to the same underground root system that continually produces new shoots and flowers that rise from the ground. Incredibly, King Clone is older than Jericho, one of the oldest, continuously-inhabited cities and King Clone was around when most of the wooly mammoths died off.

But King Clone is still a child compared to a few other clonal plants. King’s Lomatia in Tasmania has been dated to be at least 43,000 years old and thus witnessed the extinction of the Neanderthals. And a clonal grove of quaking aspen in Utah, called Pando, is at least 80,000 years old—approximately the time humans began wearing jewelry.

We have a lot to learn from plants as most humans don’t even live to 90 and there are worldwide disparities in how long humans live. Up until a few hundred years ago, the average life expectancy for a human was between 35-40 years (assuming that individual made it beyond childhood).

Today, the global average life expectancy is almost 70 years; Japan’s average is the highest at 84.2 years, and the Central African Republic and Lesotho’s are the lowest at 51.6 and 51.1 years, respectively. Even in a US city like Baltimore, neighborhood life span is disparate, ranging from the mid-80’s for some, all the way down the mid-60’s for others, which is on par with developing countries like Bangladesh. Combating the socioeconomic factors that can predominantly influence these disparities will be essential to raise the global average beyond 70.

Curiously, one creature has the luxury of ignoring most environmental factors and is considered by many to be immortal. The hydras, a group of related creatures found in freshwater bodies, do not appear to age at all. Their cells can regenerate ad-infimum and this provides strong evidence that there are genetic and biological roles in aging.

The Biology of Aging

The loss of cellular integrity and self-renewal are primary drivers of aging and lead to many of the common signs, including: wrinkles, muscle loss, bone weaknesses and frailty, graying hair, cognitive decline, and many others.

There are nine delineated “hallmarks” of aging that contribute to the decline of a cell’s ability to function. These hallmarks are: telomere attrition, genomic instability, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, stem cell exhaustion, cellular senescence, deregulated nutrient sensing, and altered intercellular communication. Usually, a combination of several of these hallmarks and phenotypes present within every individual, if not all of them at once. For those born and living in Blue Zones, it may be that protective genetic variants are more prevalent in genes related to delaying these processes.

Telomeres are the regions at the ends of all our chromosomes and they physically protect chromosomal integrity, protecting against unraveling and degradation. Each time our cells divide, the sequences of DNA comprising the telomere shorten just a little, known as telomere attrition. There is a limit to how many times a telomere can shorten, and thus a limit on how many times a cell can divide. Called the “Hayflick limit,” most cells can divide between 40-65 times, at which point the cell recognizes that its telomeres have been whittled down too far and cannot protect the rest of the genome if it were to divide again.

When a cell decides to forgo cell division, it enters a state known as senescence. Cellular senescence is the growth arrest of a cell and the number of cells within our tissues entering senescence increases as we age. Senescent cells no longer divide, but still provide functionality. As well, senescent cells may also begin to secrete inflammatory proteins and molecules that can spur inflammation nearby or systemically. This phenotype is known as SASP, or the senescence-associated secretory phenotype.

The accumulation of cells that are senescent and undergoing SASP contributes to the decline of tissue function, particularly within the heart, muscles, and immune system. And it isn’t only telomere attrition that contributes to senescence, genomic instability can also trigger cells into growth arrest.

Our cells contain a repertoire of DNA repair proteins that monitor our genome and scan it for errors. Often, mutations result from the everyday wear and tear of a cell and these accumulate cells will enter senescence as a preventative measure to protect against cancer or other types of cellular abnormalities. In fact, in most cancers, the Hayflick limit is ignored completely, as cancer cells often reactivate the ability to regenerate their telomeres and propagate other advantageous mutations. It’s no wonder that increased age is the most significant risk factor for most cancers.

Scientists have also observed that most of our tissues contain a population of stem cells to replenish the mature, functional cells that make up a majority of each tissue. For example, hematopoietic stem cells reside in the bone marrow and have the capacity to differentiate into all our white and red blood cells. This regenerative capacity keeps our immune system functional. The heart, brain, liver, and many other tissues maintain their own population of stem cells and over time they become exhausted and fail to produce new cells.

As we learn more about how our tissues and organs are organized, we’ve come to realize just how interconnected the entire body is. As more cells enter senescence and grow old, they also lose the ability to synthesize new proteins, sense nutrients and other metabolic signals around them, and/or the chemical modifications that govern how the genome is regulated can become altered and contribute to functional decline.

We also know that our cells constantly talk with one another and the communication and signaling between our tissues is essential during infection, growth and development, and to maintain systemic homeostasis. The blood and lymphatic systems of our body act as a highway of information for proteins, nucleic acids, hormones, lipids, and other material that travel the vast network of blood vessels to talk with other tissues. As we age, this communication network breaks down and it’s still unclear if this process is a cause or effect of aging.

The Modern Fountain of Youth

So, what is the magic elixir that will enable us to stretch our 150-year old legs and share stories with our great-great-grandchildren? There isn’t one, yet. Diet and exercise are tried and true methods for promoting a healthier and longer life span. It’s not a sexy answer, but reducing calorie intake extends life span in many animal models, including mice. Often referred to as caloric restriction, a reduced food load can extend the life span of worms, flies, mice, rats, and it’s thought, even humans. But does that include long bouts of fasting, or just eating less fries with that burger? A recent study published by the National Institute on Aging showed that both longer periods between meals and eating less during those meals extended the life span and health span of mice. Evidence also suggests decreasing calories can reduce the stress of cellular respiration and mitochondrial dysfunction, thereby slowing the accumulation of oxidative damage.

But what about the more provocative aging interventions? We know a variety of natural and pharmaceutical proteins and molecules are also being studied for their antiaging effects. One may well have come from the mind of Bram Stoker and his famous Dracula. Experiments show that if you infuse older mice with blood from younger mice, the aged liver and muscle tissues in the older mice will revert to a younger phenotype, with increased functionality. This was also seen in experiments in which mice were joined together and thus shared the same circulatory system.

These results spurred an international race to identify the factors in young blood that could be isolated and separately injected to reverse aging. In 2014, it was reported that a protein called Growth Differentiation Factor 11 (GDF11) can help cardiac and skeletal muscle stem cells regenerate in old mice. However, these results fell into dispute when another laboratory couldn’t replicate the findings and actually observed the opposite effect. Still another report right after claimed that a different protein called myostatin, not GDF11, was the actual antiaging miracle that researchers were searching for. Today, it’s unclear which protein factor may be useful against aging.

These findings and others have not slowed entrepreneurial interest in young blood as an aging intervention. Ambrosia LLC just completed a clinical trial studying the effects of infusing plasma from young donors into older study participants, but the results of the study have yet to be released and their company website is sparse on any further details about the results. Calico LLC was founded in 2013 and is financially supported by Google to combat aging.

Elysium, another venture, sells the dietary supplement Basis, which contains a form of vitamin B3 thought to promote cellular respiration. vitamin B3 levels drop as we age and could contribute to functional decline in our tissues. However, evidence of its use in preventing age-related declines is lacking.

And if GDF11 and vitamin B3 aren’t the answer, there are many others, including natural compounds such as tomatidine and Urolithin A, found in green tomatoes and a variety of berries, respectively. Both have been shown to improve mitochondrial function and they may even be preventative against sarcopenia, which is the age-related decline in skeletal muscle many come to experience.

Another curious molecule is called metformin. Metformin is a drug Type II diabetics use to reduce their blood sugar levels by inhibiting the production of glucose in the liver. In the US it came on the market in the 90’s and a decade later epidemiologists were shocked to observe that diabetics taking metformin had reduced mortality compared with diabetics taking other medications. Additionally, their risk for death due to cancer and cardiovascular disease was significantly reduced. Scientists have since discovered that low doses of dietary metformin can extend the life span of almost all animal models tested, including worms and mice. But how does a drug appear to slow aging, protect against cancer, protect against cardiovascular disease, all the while providing a metabolic benefit for Type II diabetics?

Metformin influences several metabolic pathways in the cell, including improving mitochondrial function, promoting cellular growth, and rebalancing energy homeostasis. Recent experiments have also shown metformin treatment can improve cellular expression of noncoding RNAs that are essential for healthy cellular function and which are known to decline in our tissues and bloodstream with age.

Metformin is particularly advantageous because it has been on the market so long that its patent has expired and generic forms have already been made available. A month’s supply can cost under $50 in the US and it would potentially be cheaper elsewhere.

Interestingly, a small FDA-approved clinical trial called the Metformin in Longevity Study was completed in May 2018. Participants over 60 years old took daily metformin for six weeks. Gene expression was measured in both muscle and fat tissue and will be assessed to see if expression is restored back to levels observed in younger individuals. Although there have been no results published to date, preliminary evidence indicates metformin treatment does affect gene expression in those tissues. Larger studies will be needed, particularly to see if low doses of metformin slow the aging process when used as a dietary supplement over a much longer duration.

Thus, while there’s currently no “cure” for aging, the future looks promising for antiaging interventions. The more that is known about how our cells and tissues decline over time, the more likely it seems that the fountain of youth may finally be discovered. Until then, it wouldn’t hurt to migrate to a Blue Zone and enjoy their ubiquitously pleasant weather, coastal scenery, and healthy lifestyle.

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