Longevity medicine has traditionally focused on prevention, examining how to minimize the factors that accelerate the body’s deterioration and keep it in good condition. Today, however, science is going one step further. Instead of asking only how aging can be slowed, researchers are investigating whether it can be reversed. Can a cell that has aged over decades return to an earlier state?
For most of scientific history, aging was considered a completely irreversible process. This belief remained firmly established until 2006, when the foundations of biology began to shift.
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Prevention vs. rejuvenation: two different directions in research
Prevention focuses on avoiding factors that accelerate aging. Rejuvenation, in turn, examines the damage accumulated in cells over the years and looks for ways to reverse it.
The difference is fundamental. Prevention works in the present: it reduces harmful processes, improves biomarkers, and slows the rate of deterioration. Rejuvenation works across time: it takes a cell in its current state and attempts to restore it to an earlier point. Prevention changes the flight path, while rejuvenation changes the starting position.
This requires entirely different tools. While prevention relies on pharmacology, lifestyle, and diagnostics, rejuvenation is based on rewriting the biological information encoded within the cell itself. That information determines the age of a given tissue.
DNA methylation patterns turned out to be the key to this information. As Dr. Dorota Komar explains in the interview “How Can Molecular Biology Help Us Manage Aging?”, epigenetics is the layer that determines gene activity. Chemical modifications of DNA change in predictable ways over time, allowing researchers to create a biological chronometer.
Horvath’s clock: from measurement to target
In 2013, Steve Horvath of UCLA published an algorithm capable of determining the biological age of tissue from DNA methylation patterns with an accuracy of several years. He focused on 353 specific locations in the genome, known as CpG sites, whose age related changes were consistent enough across tissues to form an indicator now known as Horvath’s clock1.
Initially, the algorithm served as a diagnostic tool. It made it possible to measure the difference between chronological and biological age and assess how disease or stress affected the body. We discussed this in greater detail in our article on biological age.
Over time, Horvath’s clock took on a new and revolutionary role: it became a measure of rejuvenation success. Since biological age is reflected in methylation patterns, an intervention that shifts those patterns toward a younger state effectively turns back the time recorded in cells. This effect has already been achieved in laboratories using proteins discovered by a Japanese researcher.
Yamanaka factors and cellular reprogramming: turning back the clock in living tissue
In 2006, Shinya Yamanaka demonstrated that a mature, specialized cell could be “reprogrammed” into a state in which it regained the potential to develop into any other type of tissue. This required only four proteins, Oct4, Sox2, Klf4, and c-Myc, which act as switches that activate specific genes and are now known as Yamanaka factors. When activated together, they could completely erase the cell’s identity. Yamanaka received the Nobel Prize for this discovery.
The problem with complete reprogramming was that the cell lost its specialization. It stopped being a neuron or a liver cell. Although this was an excellent solution for regenerative medicine, it was entirely unsuitable for rejuvenating the whole body.
The following decade of research produced an answer to this challenge: partial reprogramming. The goal became to reset the epigenetic marks of aging without stripping the cell of its original identity.
The first evidence of this method’s effectiveness was provided in 2016 by a team led by Juan Carlos Izpisúa Belmonte at the Salk Institute. Short term and cyclic activation of Yamanaka factors in mice improved a number of biological indicators2. The true breakthrough, however, came from a study by David Sinclair’s group at Harvard, published in “Nature” in 2020.
The researchers investigated whether aging retinal cells in mice could be rejuvenated using three of the four Yamanaka factors, known as OSK, safely delivered to the eye with AAV viral vectors. The results exceeded expectations: the cells regained electrical activity, the epigenetic clock moved backward, and some vision lost to glaucoma was restored3. This was the first time measurable tissue rejuvenation had been demonstrated in a living organism.
Senolytics: rejuvenation by clearing the tissue environment
Reprogramming renews cells from within. Senolytics work differently: they remove elements from the surrounding environment that gradually become a burden on the body.
Cells damaged by radiation, toxins, or oxidative stress naturally accumulate in our tissues. Instead of dying, they enter a kind of suspended state. They stop dividing, but they do not disappear. Science refers to them as senescent cells.
For a long time, they were considered inactive. It later became clear that they actively damage their surroundings by releasing pro inflammatory substances that harm neighboring healthy tissues and disrupt organ function. A young immune system removes them efficiently, but this ability declines dramatically with age. Their accumulation has been directly linked to lung disease, weakened bones, circulatory problems, and dementia.
Senolytics are compounds designed to selectively destroy these dysfunctional cells. Instead of acting like conventional drugs that relieve symptoms, they clear the tissues and allow them to return to more optimal function. In studies involving mice, this intervention extended median lifespan and improved physical performance. In early human trials involving patients with idiopathic pulmonary fibrosis, researchers used a combination of dasatinib, a drug used in the treatment of conditions including leukemia, and quercetin, a natural plant flavonoid. This produced a significant reduction in inflammation and improved participants’ physical mobility.
Signals of youth in the blood: lessons from parabiosis
At the same time, another field of research was developing around processes taking place directly in the blood. Scientists began analyzing differences between the plasma of young and old organisms to determine whether the substances it contains could be transferred effectively.
Parabiosis experiments, in which the circulatory systems of two mice of different ages were surgically connected, produced results that surprised even the researchers themselves. After several weeks, the older mouse connected to the younger one showed better muscle regeneration, improved liver function, and a visible improvement in cognitive performance4. Meanwhile, the younger mouse connected to the older one began showing accelerated signs of aging.
The conclusion from these observations is clear: substances circulating in the blood actively influence the pace of aging. Identifying the specific factors involved remains a major challenge. GDF11, a protein initially considered the main carrier of a “youth signal,” produced conflicting results in later studies. What is certain, however, is that the blood of an aging organism contains increasing levels of pro inflammatory molecules that disrupt signaling in tissues. Changing the composition of the blood is now one of the most promising directions in biological rejuvenation, and several biotechnology companies are currently working in this area.
Conclusions
The boundary between what is possible and impossible in the biology of aging has shifted dramatically over the past twenty years. We now know that cells can be reprogrammed into a biologically younger state without losing their identity. The epigenetic clock can measurably turn backward in a living organism under the influence of specific proteins. Senolytics clear tissues and extend the healthy lives of laboratory animals, while the blood carries signals that directly regulate degenerative processes.
Sources
- https://link.springer.com/article/10.1186/gb-2013-14-10-r115 ↩︎
- https://www.cell.com/cell/fulltext/S0092-8674(16)31664-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867416316646%3Fshowall%3Dtrue ↩︎
- https://www.nature.com/articles/s41586-020-2975-4 ↩︎
- https://www.nature.com/articles/nm.3569 ↩︎
