For people who have a few hundred thousand dollars to spend and are willing to take on the risks of an “early adopter” and travel to South America, options are now becoming available that were inconceivable just a few years ago. A new company is leapfrogging over the time-consuming process of testing and regulatory approval, and offering the best-established and most promising experimental anti-aging technologies in the near future. This is a new vision for combining research with treatment, for treating diseases that have no proven therapies, and for aging itself.
(This column begins with a couple of pages of background. If you want to cut to the chase, scroll down to BioViva.)
You only have to read Time Magazine to notice that this is the year anti-aging medicine is coming of age. Promising life extension technologies are being debuted, with potential for preventing many diseases at once, adding decades to the human life span, and restoring youthful function to an aging body. These include telomerase therapies, stem cell therapies, epigenetic reprogramming, removal of senescent cells, plasma transfer, and hormonal therapies inspired by gene expression changes between young and old.
Inevitably, this has brought a surge in the number of companies eager to jump the gun and offer treatments to consumers based on early lab research, before the technology has proved safe and effective in humans. In an age of wildcat capitalism, we are well-advised to approach all claims with a skeptical eye, and assume that hucksterism is rampant. Anyone who considers signing on with a new company that is offering a promising but unproven anti-aging technology had best start with a foundation of second opinions and broad considerations of risk and rewards.
But I stop short of saying, “stay away”. The field is too important, with too much at stake for us individually and as a human community, to sit on the sidelines, to wait for the research to be sorted out. Political control of medical research has protected us imperfectly, and has held back life-saving treatments, sometimes for decades. The system serves pharmaceutical profits more effectively than the public of medical consumers. Too often, the treatments that are approved are not those that offer the best risk/reward ratio, but those that are patentable and owned by someone who can afford to invest hundreds of millions of dollars in scientific advocacy.
The standard path to regulatory approval respects individual human life, and is “conservative” in the Hippocratic sense of “first do no harm”. But it is far from the most effective way to move science forward, and probably is not the most efficient way to save the most lives, even in the short run. Many libertarians, anti-aging enthusiasts and ordinary citizens who find themselves with a condition for which there is currently no effective medical treatment want the freedom to participate in experimental medicine, and experimental medicine certainly wants to try to help them and to learn from successes and failures.
For people who see their options for an active and creative life being closed by age-related disabilities, for people who are willing to take personal risks to help move the science forward, for people who are bold and adventure-seeking, the choice to try experimental anti-aging technologies can be a rational decision.
The Promise of Telomerase Therapies
In my opinion, the best-validated and most promising of the experimental therapies is the direct delivery of telomerase through gene therapy. This is a technology pioneered in mice by Maria Blasco’s lab in Madrid, with stunning results. In a ground-breaking 2012 paper by Blasco’s student Bruno Bernardes de Jesus, ordinary lab mice were given gene therapy with an “extra” telomerase gene spread to their cells by a genetically-engineered virus. the mice lived 13-24% longer, and the experimenters reported “remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging.”
Some strategies work better in mice than in humans, but there is theoretical reason to believe that this technique should work (even) better in humans than in mice. Untreated mice already have plenty of telomerase, and the telomeres of lab mice are at least 3 times as long as humans’, with shorter life spans in which to lose their telomeres. Before the above experiment, it was reasonable to think that telomere length was a primary aging clock in humans, but not in mice. Mice can live up to six generations after their telomerase gene has been knocked out (no telomerase at all), whereas people exhaust their telomere endowment in a single generation.
I’ve written in the past about telomere length as one of the body’s primary aging clocks. Very little telomerase is expressed in human adults. As our stem cells divide during a lifetime, telomeres get progressively shorter with age. Some results include the most important symptoms of aging:
- fewer functioning stem cells to replenish the stock of blood and skin cells
- more senescent cell, each sending out distress signals that promote the body’s hyper-inflamed state
- decline of the immune system, as new white blood cells form more slowly
- a cascade effect, as cells with short telomeres senesce and then trigger senescence in neighboring cells
- higher cancer rates, as the chromosomes in cells with short telomeres become unstable, and the immune system sentinels that nip cancer in the bud go AWOL.
Yes—higher cancer rates result when telomeres get short. There is a theory that our bodies withhold telomerase in order to prevent cancer, but it is an idea with no experimental support. Fear of cancer has held back telomerase therapy, and this is a red herring, based on misunderstanding of evolutionary biology. All evidence suggests that telomerase therapies will lower cancer risk.
- a lab that provides genetically modified viruses with a gene payload, made to order. (This has now become a reliable and predictable technology.)
- A doctor who has experience with experimental gene therapy, and who had the courage to experiment on himself five years ago, with good outcome thus far.
- Sites in Colombia and Mexico where doctors will administer therapies for which there is not yet FDA approval.
- Most important, a Scientific Advisory Board that includes two of the most prominent, senior biochemists who developed the science of telomerase in the 1990s and before. They are Bill Andrews and
Michael Fossel. [This was my error when I wrote up the article. Fossel is not on the advisory board of Bioviva. The board is listed here, and as of 2016Feb, it includes George Church and Bill Andrews].
What they offer is gene therapy with hTERT and a proprietary myostatin inhibitor “in the same family with GDF-11,” according to CEO Elizabeth Parrish.
Parrish stresses that AAV gene therapy is a mature technology and has already passed FDA tests for safety. “AAV has become increasingly common as a vector for use in human clinical trials; as of , 38 protocols have been approved by the Recombinant DNA Advisory Committee and the Food and Drug Administration (FDA).” [ref] The uncertainties are no longer about safety, but about whether the virus will be destroyed by the body’s immune system before their payload can be delivered. The rejuvenation benefit is likely to be systemic, and will have ripple consequences that we can only learn with human subjects.
In a surprise marketing move, Parrish has offered a guarantee for Patient #1 only. If results for the first patient are disappointing, and Bioviva learns to avoid pitfallss and do a better job over the next 2 years, Patient #1 will be re-treated without cost, using the updated technology.
How Gene Therapy Works with AAV
AAV stands for Adeno-Associated Viruses, and there are several types in use. This virus makes its living by
- slipping its payload of DNA into a human cell (shedding its protein shell at the cell wall)
- finding its way to the cell nucleus
- copying itself into a specific place on Chromosome 19,
- from where it manufactures copies of its own DNA, and also of the proteins that it needs to replicate, to penetrate other cells.
In therapeutic applications, the AAV DNA strand is modified to include a payload of therapeutic DNA, and to eliminate the genes coding for proteins that AAV needs in order to reproduce. In this form, the modified virus can infect a cell, but once inside it cannot reproduce, infect more cells, reproduce there, and spread, causing disease. It becomes a one-trick pony. Each individual virus can infect one cell only, and then it has shot its wad. No way this infection can “go viral”.
AAV therapy has been studied for over 25 years, and there is some reason to expect that the payload gene can remain active for a long time. So this is a permanent change in the DNA of some cells in the body, though it is not a permanent infection. Though AAVs are common in the environment, 80% of us have a naive immune response, so the treatment can be effective. (For the other 20%, temporary immune suppression may be necessary.) Repeat treatments are sometimes possible. Here is a good semi-technical introduction to the subject.
Adeno-associated viruses, from the parvovirus family, are small viruses with a genome of single stranded DNA. These viruses can insert genetic material at a specific site on chromosome 19 with near 100% certainty. There are a few disadvantages to using AAV, including the small amount of DNA it can carry (low capacity) and the difficulty in producing it. This type of virus is being used, however, because it is non-pathogenic (most people carry this harmless virus). In contrast to adenoviruses, most people treated with AAV will not build an immune response to remove the virus and the cells that have been successfully treated with it.
Different AAV viruses can be customized to infect different cell types, and of course the place where the virus is injected is the most likely place for the virus to take root. Viruses used in previous generations of gene therapy tended to disrupt the body’s own DNA by inserting at sites that are essential, and cancer rates were raised by some early forms of gene therapy. AAV is favored because its target site seems to be safe, and its insertion harmless.
Therapies with hTERT and Myostatin Inhibitor
hTERT is only half the telomerase molecule, but it is the half that is in short supply, and hence the bottleneck for production of telomerase. Of course, the DNA in our every cell contains the hTERT gene, but it is covered up and remains un-expressed almost all the time. The new copy on Chromosome 19 is active, and in tests in cell cultures and live mice, telomeres have been lengthened.
I believe that telomerase is the closest thing we have at present to a cure for aging. Bill Andrews and others have a long-term goal of developing drugs that will signal the body to activate its own telomerase gene, but these seem to be a few years off. For now, adding an extra gene for hTERT may be the most promising generalized anti-aging intervention. An important issue is that a large viral dose may be needed to saturate the body’s stem cells with the gene payload. This is because a small minority of cells with the shortest telomeres is the source of some of the body’s biggest problems. We’ll learn about the body’s response—if we are lucky, a rejuvenated immune system will itself eliminate the residual senescent cells without the need to lengthen telomeres in every senescent cell.
The myostatin strategy grows from (of all things) body-enhancement strategies for muscle-builders. Myostatin is a member of the TGF-β family, is also called GDF-8*, and is a gene that inhibits muscle growth. So if myostatin can be tied up, there is less inhibition and more muscle growth. In the last several years, creatine has become a popular supplement for body-builders, and it works directly at the level of the gene, by inhibiting expression of myostatin=GDF-8. Later in life, expression of the myostatin gene increases, and it is thought, logically enough, that this is a cause of the loss of muscle mass (sarcopoenia) that is almost universal with aging (though it is mitigated by exercise). Bioviva offers gene therapy for a myostatin inhibitor (the specific gene is not disclosed), and it has been tried by one of the team members, experimenting on himself 5 years ago, with good results in a younger man. Here is an article that offers a balanced view of reasons to believe this might or might not work for age-related sarcopoenia.
Perhaps more important, the same gene has been found to clear blocked arteries, with expected reduction of the risk for heart disease and stroke. There is rodent data and good theoretical reason to expect this will work, and there has been one heart patient who has received the AAV/myostatin treatment it with excellent results. Blocking myostatin is also expected to reduce the progression of insulin resistance that is a driver of many age-related diseases.
There is a well-supported theory of AD that it has its roots in the microglial cells of the brain. These are not nerve cells, but they act as a kind of immune system for the brain, protecting it from inflammation and cleaning up plaques. Their secretions promote growth and repair. Unlike nerve cells, microglia are continually replicating, and so they lose telomere length over time. On the theory that restoring telomeres in the microglia will reverse dementia, Bioviva is offering gene therapy with hTERT in the brain as treatment for AD. Direct evidence that this might work comes from a 2011 experiment from the de Pinho lab at Harvard Med School, in which brains atrophied in mice deprived of telomerase, and the brains actually regrew when telomerase was provided.
The Bottom Line
Experimental treatments are, by definition, at the wrong end of the learning curve. But there is so much to be gained, and the people involved are such experts, that I am deeply hopeful about Bioviva’s work, and the prospect of a fast track to meaningful anti-aging therapies.
* Myostatin is GDF-8, not to be confused with GDF-11, which has also been recently in the news. Both are in the TGF-ß family. GDF-8 inhibits muscle cell growth, while GDF-11 inhibits nerve cell growth. Curiously, Bioviva’s anti-aging strategy is to suppress GDF-8 but last year’s headline-making paper from Harvard found benefits in promoting GDF-11.