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.