The reason the body has multiple, redundant aging clocks is to assure that natural selection can’t defeat aging by throwing a single switch. That means the clocks must be at least somewhat independent. Nevertheless, I judge it is likely that there is some crosstalk among clocks, because that’s how biology usually works. To effect rejuvenation, we will have to address all aging clocks, but we see some benefit from resetting even one, and expect more significant benefit from resetting two or more.
The most challenging target is the epigenetic clock,built on a homeostasis of transcription and signaling among hundreds of hormones that each affect levels of the others. Reverse engineering this tangle will be a bear.
The idea of a centralized aging clock in the hypothalamus seems far more accessible, and is promising for the medium term. Still, it does not suggest immediate application to remedies. The hypothalamus is deep in the brain, and you and I might be reluctant to accept a treatment that required drilling through the skull. A treatment based on circulating proteins and RNAs from the hypothalamus would be less invasive, but even that might have to be intravenous, and include some chemistry for penetrating the blood-brain barrier. RNA exosomes seem to be our best opportunity
As Cavadas’s group has already pointed out, it is inflammation in the hypothalamus that is amplified by signaling to become most damaging to the entire body. This raises the interesting question: could it be that the modest anti-aging power of NSAIDs is entirely due to their action within the brain? In other words, maybe “inflammaging” is largely localized to the hypothalamus.
The researchers, from the Mayo Clinic in Rochester, Minnesota, are calling for senolytic drugs to make the leap from animal research to human clinical trials. They outlined potential clinical trial scenarios in a paper published in the Journal of the American Geriatrics Society on Monday.
"This is one of the most exciting fields in all of medicine or science at the moment," said Dr. James Kirkland, director of the Kogod Center on Aging at the Mayo Clinic and lead author of the new paper.
As we age, we accumulate senescent cells, which are damaged cells that resist dying off but stay in our bodies. They can affect other cells in our various organs and tissues. Senolytic drugs are agents capable of killing problem-causing senescent cells in your body without harming your normal, healthy cells.
Scientists have long known that certain processes influence your body's aging on the cellular level, according to the paper. Those processes include inflammation, changes in your DNA, cell damage or dysfunction and the accumulation of senescent cells.
It turns out that those processes are linked. For instance, DNA damage causes increased senescent cell accumulation, Kirkland said.
So an intervention that targets senescent cells could attenuate other aging processes as well, according to the new paper. That is, once such an intervention is tested for efficacy and safety.
"I think senolytic drugs have a great future. If it is proven that it can reduce senescent cells and rejuvenate tissues or organs, it may be one of our potential best treatments for age-related diseases," said Dr. Kang Zhang, founding director of the Institute for Genomic Medicine at the University of California, San Diego, who was not involved in the new paper.
Yet taking senolytic drugs from mouse studies to human ones is a "big leap," Zhang said.
"So we will have to wait for clinical trials to see whether this would work in humans," he said. "One possible clinical trial strategy is to test this class of drugs in an age-related disease, such as neurodegeneration, like Parkinson's disease, to see if it can reduce clinical severity of the disease and improve tissue functions."
Senescent cells play a role in many age-related chronic diseases, such as diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis and blindness, Kirkland said. Therefore, senolytic drugs are a possible treatment approach for such diseases.
As a practicing physician, Kirkland said that he has grown increasingly concerned for his patients who are sick with many of these age-related conditions.
"The same processes that cause aging seem to be the root causes of age-related diseases," he said. "Why not target the root cause of all of these things? That would have been a pipe dream until a few years back."
One company, Unity Biotechnology, aims to be the first to demonstrate that removing senescent cells can cure human diseases, said its president, Nathaniel David.
"In the coming decades, I believe that health care will be transformed by this class of medicine and a whole set of diseases that your parents and grandparents have will be things you only see in movies or read in books, things like age-associated arthritis," said David, whose company was not involved in the new paper.
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish. An experimental "longevity" drug that recreates the effect of the mutation is now being tested in human trials to see if it provides protection against some aging-related illnesses. Indiana Amish kindred (immediate family and relatives) with the mutation live more than 10 percent longer and have 10 percent longer telomeres (a protective cap at the end of our chromosomes that is a biological marker of aging) compared to Amish kindred members who don't have the mutation.
Amish with this mutation also have significantly less diabetes and lower fasting insulin levels. A composite measure that reflects vascular age also is lower - indicative of retained flexibility in blood vessels in the carriers of the mutation - than those who don't have the mutation. These Amish individuals have very low levels of PAI-1 (plasminogen activator inhibitor,) a protein that comprises part of a "molecular fingerprint" related to aging or senescence of cells. It was previously known that PAI-1 was related to aging in animals but unclear how it affected aging in humans.
"For the first time we are seeing a molecular marker of aging (telomere length), a metabolic marker of aging (fasting insulin levels) and a cardiovascular marker of aging (blood pressure and blood vessel stiffness) all tracking in the same direction in that these individuals were generally protected from age-related changes. That played out in them having a longer lifespan. Not only do they live longer, they live healthier. It's a desirable form of longevity. It's their 'health span.'"
The researchers have partnered with another group in the development and testing of an oral drug, TM5614, that inhibits the action of PAI-1.
As this Weizmann Institute story explains, Tzahor’s team has shown that activating a specific gene (ERBB2) following a heart attack can “nearly completely heal a heart within several weeks.” In other words, stem cells with embryonic healing capabilities are activated to repair cardiac damage.
Tzahor said, “As opposed to extensive scarring in the control hearts, the ERBB2-expressing hearts had completely returned to their previous state.” He also said, “The results were amazing.”
Amazing is an understatement. Seen narrowly, a drug that Tzahor is developing could directly address our biggest cause of death, heart disease.
Most heart attack victims survive, though with permanently reduced health. Tzahor’s goal is to restore damaged hearts to perfect health. Even patients who would otherwise die could be put on life support for a few weeks while their hearts healed.
Beyond the humanitarian benefits, the healthcare cost savings would be huge. The combined direct and indirect lifetime cost of a heart attack in the US is about $1 million. According to the CDC, there are about 580,000 first heart attacks every year.
Multiply those two numbers and the result is $580 billion. A drug capable of curing or preventing heart disease could yield more than half a trillion dollars in medical savings annually.
Last week, the world got the first peer-reviewed look at what I believe is the future of medicine. Specifically, I’m talking about the discovery that the COX7A1 gene is a switch that controls embryonic healing processes.
The genes that built you from a few undifferentiated embryonic cells are still in your genome. These “developmental” genes are largely dormant, but they’re still there.
In the last year, about half a dozen institutions have announced breakthroughs in the reactivation of these genes. However, not much has been revealed about what’s happening on the genomic level.
That’s why the publication of a paper in the respected journal Oncotarget is historic. The article is titled, “Use of deep neural network ensembles to identify embryonic-fetal transition markers: repression of COX7A1 in embryonic and cancer cells.”
The paper presents the culmination of research I’ve been writing about for several years. Having pioneered work on the immortalizing enzyme telomerase and pluripotent stem cell medicine, Michael West, CEO of both BioTime and its subsidiary, AgeX Therapeutics, has taken regenerative medicine to the next level.
This paper is the first peer-reviewed evidence that the genetic blueprint active in the first stages of life remains accessible in adults. Though I consider West the leader in this field, he’s not the only scientist working on reactivating embryonic gene pathways. I think that’s a good thing because it’s unlikely that anybody would believe a single scientist presenting evidence that the damage caused by aging and trauma is reversible.
Induced Tissue Regeneration
This is the basic idea: While we’re in the embryonic stage, our bodies deal with injuries by going back to the original genetic blueprint. Until humans transform from the embryonic state to the fetal or adult state—at about the eighth week following conception—we draw on our genetic blueprint to fix problems.
Once we’ve reached the adult or fetal stage, that changes. Cells then replicate by copying their existing genetic state. If there is an injury, surrounding cells adapt via processes like scarring, but defects can be passed on. As we age, those defects multiply.
Though embryonic healing powers are mostly dormant in adults, they still exist in our genomes. It they could be reactivated in adults, damaged organs and tissues could regenerate based on their original genetic blueprint. West refers to the process as induced tissue regeneration (iTR).
While this stretches the imagination, it’s a fact that many animals maintain active developmental genes throughout their lives. When these animals are injured, they draw on their embryonic gene instructions to regenerate damaged limbs and organs.
One animal that maintains embryonic powers is the Iberian ribbed newt (Pleurodeles waltl). Researchers at the Swedish Karolinska Institutet recently sequenced the animal’s genome. Among the most important discoveries was a profusion of genes normally active only in the embryonic stage.
The purpose of the research is to shed light on how certain animals access developmental gene pathways for regeneration. The lead scientist, Professor András Simon, told Phys.org, “It will be exciting to figure out how regeneration in the adult organism re-activates embryonic genes.”
Indeed, the implications of iTR in humans are staggering. Skin, hearts, eyes, pancreases, joints, even brains could be rejuvenated if the genetic code were found to unlock iTR. Aging itself could be reversed.
The Oncotarget paper by West et al. that I mentioned above indicates that a major part of the code has, in fact, been found. As the title of the paper indicates, the COX7A1 gene plays a central role in suppressing developmental pathways. More importantly, the paper provides evidence that blocking the gene allows access to the embryonic blueprint.
The gene’s name, by the way, is a shortened version of Cytochrome C Oxidase Subunit 7A1. As the GeneCards entry explains, it is the terminal component of the mitochondrial respiratory chain.
That’s fascinating because mitochondria provide the energy necessary for biological complexity. Without mitochondria, animal life would be limited to the most primitive forms.
The tradeoff, however, is that mitochondrial energy production seems to shut down embryonic gene pathways. In fact, during our embryonic phase, we don’t rely on mitochondrial oxidative phosphorylation. This is possible because the embryo uses the mother’s metabolism.
We also know, thanks to the Oncotarget paper, that the COX7A1 gene is turned off in embryonic cells. It’s worth noting how this discovery was made.
Using advanced artificial intelligence technologies, West and scientists from InSilico Medicine analyzed the genetic changes that take place when cells change from embryonic to adult.
COX7A1 seems to be a kind of bookend to telomerase. For cells to be immortal, the telomerase gene must be active. For cells to function with full access to their embryonic blueprints, COX7A1 must be suppressed. When adult cells are reverted to their embryonic state using genetic engineering, COX7A1 is turned off.
Incidentally, you might check out figure 3A in the Oncotarget paper. On the far right of the graph, you can see COX7A1 gene expression levels in three men in their 60s. Their “reprogrammed” iPS cells have returned to embryonic status.
Those three cell lines are West’s, mine, and John Mauldin’s. John and I donated our cell lines for just this sort of research.
All of this indicates that it is theoretically possible to activate developmental pathways in humans for medical purposes. The most radical implication, of course, is the possibility of age reversal.
Ultimately, this will happen. And it will profoundly change the human experience. I believe that people who are young today will routinely access their embryonic gene pathways to cure disease and the symptoms of aging. Does that mean my generation will be the last to die of old age?
When West and his team found the COX7A1 embryonic gene switch, they wondered if any existing compound hit the right target. InSilico Medicine maintains a vast library of information about the genetic effects of existing compounds. Using AI tools, they identified a drug that suppresses COX7A1.
I spoke with Dr. West about this drug, but he wouldn’t tell me all the details. The reason is that he’s still putting together a patent library to cover its use for regenerative medicine.
This is what we know now: The drug is well-known and extremely safe. It’s also off-patent, available as a generic, and widely used. He said I would never guess what the drug is because its approved use has nothing to do with regenerative medicine.
This isn’t particularly surprising. Increasingly, we are seeing old drugs used successfully for completely unexpected conditions.
He also told me that the drug is not a perfect COX7A1 switch, which remains his primary quest. In the meantime, however, this drug (which he’s calling Renelon) works well enough to warrant commercialization.
So far, all we know for sure is that he intends to deliver the drug locally in a biological device. The device is synthetic extracellular matrix (ECM). ECMs are biological scaffolding made of naturally occurring molecules.
I asked West what tissues he intended to target with Renelon. The obvious big target is the heart since cardiac disease is our biggest killer. Scientists at the Weizmann Institute in Israel are also looking at activating embryonic pathways to repair damage caused by heart attacks.
On the other hand, a topical skin rejuvenation product would probably be easier and cheaper to get to market. I don’t really care about appearances that much, but such a product could quickly fund West’s research into more important problems, including aging.
West’s answer to my question was interesting. He said he hadn’t decided yet what condition to target with Renelon. That means he has options and indicates that the drug could work systemically. It might, in fact, be an effective geroprotector or anti-aging compound.