Original article here

by Gabriel Filsinger
figures by Anna Maurer

Can biological aging be slowed or reversed?

Time is constantly passing. Given enough time, we change as people and move between stages of life, transforming from children into young adults and evolving from parents into elderly grandparents. Although we may not notice it explicitly, time continually and unrelentingly propels us forward into the future. To us, time and age are linked. Like time, aging is thought to be an irreversible feature of life. However, researchers have been continuously searching for methods to slow or reverse aging and its effects.

Although a number of therapies are being pursued that could treat aging in humans, even the most promising techniques would only provide moderate benefits to human health and lifespan. None of the current procedures being tested or explored reverse the fundamental causes of age-related health decline.

Reprogramming, on the other hand, allows scientists to completely reverse the effects of aging, at least on a cellular level. In this method, four proteins are added to older cells to reset them to an embryonic-like state, and it is one of the unique examples of procedures that reverse cellular age. By applying insights gained from reprogramming, it might be possible to more profoundly understand and manipulate what happens as we age.

Most of the current therapies to slow or reverse aging only have moderate effects in mammals

Within the last decade, technologies that aim to reverse aging in humans became a major target for investment, but little of this investment has been directed toward reprogramming. In 2013 Google founded it’s own biotechnology company called Calico in order to develop tools that extend lifespan, and in March 2016, Fortune published an article titled “6 Entrepreneurs Working on Cures for Aging”, which included Peter Thiel, the co-founder of PayPal and Palantir, Bill Maris, the president of Google Ventures, and Craig Venter, an scientist who spearheaded the original effort to sequence the human genome.

This recent interest in aging therapies has been spurred by experiments in mice and other model systems that result in moderate improvements to lifespan and reversal of age-related cognitive decline. While turning the tools used in these experiments into therapies that work in humans could undoubtedly lead to huge improvements in late-age quality of life, there are no examples of treatments that can reverse the age of a whole organism like reprogramming can do for single cells. The set of existing therapies, even in model systems, only delay the inevitable: a slow but irreversible degradation of health and fitness. For scientists that are interested in more fundamentally reversing age, results in single cells might hold the key for understanding how to do so.

Reprogramming makes old cells young again

In June 2007, three separate research groups showed that old cells could be reverted to a youthful state through reprogramming (1, 2, 3). The researchers took old skin cells of adult mice and added 4 proteins called Yamanaka factors. These newly reprogrammed cells lost all the features of age and instead of old skin cells, acted like cells obtained from an early embryo. These new cells could even be implanted in female mice to form a new baby animal, which was able to grow and develop normally.

Reprogramming reset all of the old skin cell’s original aging markers, including reduced telomere length, epigenetic features, and unhealthy mitochondria and the old skin cell became an embryonic-like cell. Although this result is relatively spectacular it would never work as a therapy. Directly reprogramming the body’s cells would be too extreme to be used as a feasible treatment: you wouldn’t want your skin cells to lose all their skin features and instead become like the identity-less cells of an early embryo. However, could concepts learned from reprogramming be used to inform subtler aging reversal therapies?

Reprogramming resets age by resetting a cells epigenetic state, so it might be possible to directly manipulate epigenetics and match the anti-aging results of reprogramming. Epigenetics describes changes to a cell’s genes that are not changes in the actual sequence of the DNA. This could include, among other things, changes in how the DNA is packaged in the cell or physical modifications to the DNA molecule that do not change its sequence. Unlike changes to DNA’s sequence, epigenetic changes are reversible. By resetting only a few epigenetic changes, it might be possible to reverse the symptoms of age without changing cells into embryonic-like cells.

Scientists have successfully reprogrammed old cells to stem cells, and then differentiated these stem cells back to their tissues of origin. These reprogrammed cells have the characteristics of young cells, which suggests that the characteristics of aging can be reversed. “Partial reprogramming” would be ideal for combating aging, in which old cells are converted directly to young cells without a stem cell intermediate.
Scientists have successfully reprogrammed old cells to stem cells, and then differentiated these stem cells back to their tissues of origin. These reprogrammed cells have the characteristics of young cells, which suggests that the characteristics of aging can be reversed. “Partial reprogramming” would be ideal for combating aging, in which old cells are converted directly to young cells without a stem cell intermediate.
The jellyfish Turritopsis dohrnii uses reprogramming to become biologically immortal.

Although reprogramming works to reverse age of a single cell, there is also an example of a similar type of reprogramming working to reverse the age of an entire organism. As a second indication that reprogramming is key to age reversal, scientists have found that the technique is used by the jellyfish Turritopsis dohrnii to stay immortal. This animal has been reported to have a seemingly infinite lifespan, and is one of the only organisms on the planet with this property.

Interestingly enough, as opposed to being resistant to the processes of time, this jellyfish lives forever by constantly transforming into an immature state. If the jellyfish is sick or old, it performs a transformation act and reverts all of its cells from an adult state into an earlier developmental form called the “polyp” state, much like what happens during reprogramming of single cells. Once in the polyp state, the jellyfish can then re-mature as a healthy adult. Because it can do this continuously, the jellyfish theoretically has an immortal biological age.

While this also would not directly work as a therapeutic strategy in humans, it further indicates that resetting cell state through reprogramming can be used to reverse age within a living organism, and by exploring reprogramming, we might learn how to truly replenish health and fitness.

How can reprogramming be developed into a therapeutic or research tool?

Minimally, reprogramming should be used to help identify what affects the aged state of cells. By comparing old cells with reprogrammed cells from the same patient, it might be possible to identify sets of epigenetic changes that occur with age, and specifically target and revert them to recover cellular health. To do this, scientists have taken old skin cells, reprogrammed them into young embryonic-like cells, and then turned these cells into skin cells. The final product is a young skin cell, which can be directly compared with old skin cells from the same patient. By analyzing the differences, it might be possible to understand what changes could be reversed to only reset age.

The ideal reprogramming therapy would be a method that resets cellular age without fully reverting the cell to an embryonic-like state. While this currently hasn’t been found, epigenetic drugs such as Remodelin have been shown to influence DNA packing, and similar strategies using CRISPR to affect epigenetics could be used to search for targets that reverse aging but don’t cause reversion to an embryonic-like state.

One futuristic application of reprogramming would be to develop new organs from a patient’s old cells, which if grown in a lab or model organism, would be identical to the patient’s organs but younger. These new organs could then be transplanted back into the patient to replace their old or damaged tissue.

Although reprogramming’s effect on aging is still too mysterious to be directly transferred into a therapy, it is the only method known to truly reverse age on a cellular level, and the insights it reveals may one day lead to more radical therapeutic treatments.

Gabriel Filsinger is a 3rd year graduate student in the Systems Biology program at Harvard University.