The Hayflick Limit: why humans can't live forever

 A scientific legend, Leonard Hayflick, passed away at the beginning of August. Most non-scientists probably don’t recognize his name, but he made a remarkable discovery in the early 1960s. Back then, while doing experiments on human cells, he and a colleague, Paul Moorhead, discovered that our cells can only divide a limited number of times.

This discovery, although made at the level of an individual cell, has a dramatic implication: humans cannot live forever.

What Hayflick discovered was that after 40 to 60 rounds of splitting in two, cells simply won’t divide any more. At that point, they enter a phase called senescence, and they eventually die. The number of divisions that a cell can go through is now known as the “Hayflick limit.”

Prior to Hayflick’s experiments, many scientists believed that cells could divide forever. After all, every cell in our body comes from one original cell, and that cell came from our parents, and from their parents before that, and so on back through the ages. So it stood to reason that cells could continue to divide without limit. What’s more, in the early 20th century, Alexis Carrel (a Nobel laureate) claimed to have grown cells in his labs that continued to divide for decades, with no sign of decline.

(Aside: Jan Witkowski explained in an article back in 1980 that it was likely that Carrel’s seemingly immortal cells had been quietly replenished, without Carrel’s knowledge, by members of his lab who were eager to keep the boss happy.)

Back to the Hayflick limit: because all of our organs are destined to wear out, our bodies will simply die unless we can intervene and restore cells to their youthful state. That would require technology that has not yet been invented. Hayflick himself estimated that the limit of the human lifespan is 125 years.

Hayflick’s limit raised an intriguing puzzle: how does a tiny, microscopic cell keep track of how many times it has divided? In other words, how can a cell know how old it is? Don’t all of our cells have identical DNA? Hayflick himself didn’t have a solution for this, but a few decades later, others figured it out.

The answer to this cellular “clock” puzzle resides, it turns out, in our DNA. More specifically, it depends on the DNA sequences at the very ends of our chromosomes, which are called telomeres.

Telomeres don’t really do anything, and they appear very simple: they consist of a long stretch of six DNA bases, TTAGGG, repeated hundreds of times, end-to-end. All our chromosomes end with telomeres, on both ends.

So here’s the thing: when a cell divides, it has to copy all of its chromosomes. The mechanism for copying isn’t quite perfect, and it can’t go all the way to the end of the chromosome, so the new copy is a little bit shorter. The telomere gets shorter! Fortunately, we have a special enzyme, called telomerase, that fixes this problem by adding a few extra copies of TTAGGG to the end of each chromosome, restoring the proper length. Problem solved, right?

Well, no. Telomerase doesn’t work perfectly, and chromosomes sometimes do get a bit shorter each time they divide. When the chromosomes get too short, the cell can’t divide any more, and it eventually dies.

And yes, scientists have explored the question of whether telomere length might be the key to longevity. No one has figured out a way to keep telomeres long, and it’s not clear that would help anyway. On the contrary, as my Hopkins colleague Mary Armanios reported in a study last year, long telomeres might help individual cells stick around, but they don’t seem to prevent aging.

Does the Hayflick limit mean we really can’t live forever? Well, not necessarily. Some types of stem cells can produce “fresh” cells that could, in theory, replenish our old cells. Perhaps some day we’ll have the technology to replace our organs with new ones, possibly grown in a lab, that will have the youth and energy of a 20-year-old. But without replacing our parts, we are destined to wear out, even if we manage to avoid cancer, infections, and the many other perils that humans face.

Leonard Hayflick made it to 96, a ripe old age by today’s standards. It would have been fitting if he’d reached 125, the limit that he estimated, but no human has ever done that. Yet.

Did a biotech CEO successfully reverse her own aging process? Maybe not.

Elizabeth Parrish, CEO of BioViva.

Humans have been searching for the fountain of youth for millenia, dating back to ancient times. No one has found it yet, so I was very skeptical when I saw the recent announcement from BioViva, a biotech company, of what they called the first successful gene therapy against human aging:

"Elizabeth Parrish, CEO of Bioviva USA Inc., has become the first human being to be successfully rejuvenated by gene therapy, after her own company's experimental therapies reversed 20 years of normal telomere shortening."

That's quite a dramatic claim. If true, this would be a historic breakthrough: no one has ever reversed aging before. While human life expectancy has doubled over the past 150 years, virtually all of this progress has been from preventing early deaths, thanks to the developments of antibiotics, vaccines, and public health advances such as clean water.

Human life expectancy has doubled since the 1840's.
Figure source: Natl Institute on Aging.

Most claims about anti-aging therapies are easily dismissed as pseudoscience, nonsense, or scams. Not this one, though. BioViva has two experimental therapies, both based on legitimate science, and both with at least a chance of working. Neither has yet been proven to work in humans, but both are plausible.

According to BioViva and to interviews with its CEO, Elizabeth Parrish, Parrish received two therapies last year, one to protect against the loss of muscle mass, and one to lengthen her telomeres. The recent announcement claims that the telomere-lengthening therapy is already working, so I looked a bit deeper to understand what might be going on.

First a bit of background: telomeres are special DNA sequences that act as "caps" on both ends of every chromosome, providing a kind of protection for your genes. Each time a cell divides, its telomeres get a little bit shorter, and eventually they get too short and the cell dies. Telomeres therefore act as a kind of molecular clock that tells a cell how old it is. Our cells also have a special enzyme called telomerase that rebuilds telomeres. Cells with lots of telomerase can live much longer, and those without it die more quickly. Discovering how this all worked was a tremendous scientific achievement, for which Elizabeth Blackburn, Carol Greider, and Jack Szostak received the 2009 Nobel Prize.

Scientists have been speculating for years that telomerase might somehow hold the key to aging. BioViva's gene therapy delivers telomerase to the blood with the help of weakened viruses called adeno-associated viruses (AAVs), which they modified to carry the telomerase gene. The virus infects human cells and releases its payload into them, where the "transgene" produces extra telomerase.

This may sound very nice, but it's really, really complicated in practice. Gene therapy can have unexpected negative effects, and no human trials have yet shown that anyone can deliver telomerase effectively to human cells. However, studies in mice have shown some remarkable results: in 2012, a group of scientists at the Spanish National Cancer Centre used AAV to deliver telomerase to mice, and found that it "had remarkable beneficial effects on health and fitness" and that

"telomerase-treated mice, both at 1-year and 2-years of age, had an increase in median lifespan of 24 and 13%, respectively."

This exciting scientific result, and a few others like it, are what led BioViva and Elizabeth Parrish to try the same therapy in humans.

But did it work? Well, this is where things get a bit fuzzy. BioViva claims it did, based on their measurements of the length of telomeres in Parrish's white blood cells in September 2015, before therapy started, and again in March 2016. They claim that her telomeres got longer, from 6.71 kilobases (a kilobase is 1000 DNA letters) to 7.33 kilobases. This increase corresponds to about 20 years of aging: in other words, Parrish's white blood cells "have become biologically younger," as the company reported.

Setting aside the problem that we cannot really conclude anything from an experiment involving only one person, we can still ask: did Parrish's telomeres really get longer? As much as I want to believe BioViva's claim, there are several rather serious problems here. First, the company itself reported that Parrish's telomeres were unusually short for her age before the experiment began. Does this mean that the measurements were simply a bit off, and the second measurements were closer to the true number? Second, as UCLA's Prof. Rita Effros explained in an interview at geneticexperts.org,

"The overarching problem is that peripheral blood contains a mixture of many different cell types with disparate telomere lengths.... Thus, a simple change in the proportion of different cell types within the peripheral blood could easily explain the data."

In other words, it's possible that Parrish's telomeres did not get any longer. Despite the apparently precise numbers, BioViva has not provided any details showing that these measurements are accurate and reproducible (and they didn't respond to my request for these details). Their claim might be much more convincing if they made multiple measurements, both before and after treatment, and if these measurements showed that Parrish's telomere lengths really did increase.

There are a number of red flags about BioViva itself. Parrish herself is not a scientist, though she is an eloquent spokesperson for her company's therapies. More concerning is their Chief Medical Officer, Jason Williams, who previously ran "a dubious stem cell clinic," Precision StemCell (now located in Mexico) that offers stem cell therapies to patients with ALS (Lou Gehrig's disease), for which there is no evidence that they work. Personally, I would not trust Dr. Williams with my medical care.

The bottom line is that we simply don't know if BioViva's treatment worked on Elizabeth Parrish. They need to produce more data, on more patients, to construct even a mildly convincing scientific argument. Getting more patients may be very difficult, though: Parrish bypassed FDA regulations by traveling outside the U.S. (to Colombia) to conduct this experiment on herself.

Telomerase treatment to reverse aging is very promising, and it might really work, someday. I sincerely hope it will.  For now, though, BioViva's announcement leaves me very skeptical.