In the dystopian movie The Island starring Ewan McGregor and Scarlett Johansson, clones of regular people are grown as a source of replacement body parts for ailing DNA-matched clients — wealthy people willing to pay large sums of money to extend their lifespans.
Ethics aside, this premise begs the question: Can we live forever if we keep replacing our body parts?
Perhaps, since we have the option to become donors, it’s more realistic to ask: Are there factors of donor organs that influence the recipient’s aging process that can make us biologically younger or older?
Donor young and old cells that are transplanted appear to be capable of regulating aging by influencing the cells in the recipient.
On the one hand, young donor cells have been shown to have the capacity to promote regeneration in recipient tissue, and, on the other hand, old donor cells can induce the aging of neighboring cells and adopting tissues in recipients. These effects are not limited to the immediate surroundings but can work to have effects all throughout the body.
So, how did scientists figure this out?
Initial insights into the consequences of combining cells from animals of different ages were predominantly investigated in experimental models called heterochronic parabiosis. This is when the circulatory systems of animals of different ages are joined. In other words, two animals get surgically linked together like siamese twins with shared blood.
Interestingly, reciprocal effects occur between the young and old conjoined animals. With the circulatory connection, the younger animal becomes older, and the older animal becomes younger. In this conjoined setting, several organs, such as the liver, brain, and cardiovascular systems, undergo age-associated changes, pointing to factors in the blood that can influence aging.
Heterochronic parabiosis studies (and subsequently more refined studies) have opened a new vein of aging research, and one with therapeutic potential. An obvious potential therapeutic direction involves direct transfusion of blood or plasma alone from young people, which may be sufficient to transfer factors that confer rejuvenation or aging.
There are a couple of alternative approaches. One involves identifying rejuvenation factors in blood from young people and supplying them directly. Conversely, we can try to identify aging factors and selectively remove them. Another direction would be via therapeutics that target non-replicating, growth-arrested senescent cells, as these cells may be involved in the production and secretion of many of these aging and often inflammatory factors.
(Science) Heterochronic parabiosis. This surgery, whereby the circulatory systems of two animals are conjoined, leads to the cross-circulation of factors and cells via shared blood. Typically, two animals of different ages are joined to test for systemic regulators of aspects of aging or age-related diseases. Studies have shown that older mice conjoined with younger mice see improvements in blood flow and olfaction as well as boosts to brain stem cell proliferation and skeletal muscle rejuvenation.
Blood-derived factors may not be the only way by which aging traits are transferred. Grafts from older individuals show inferior outcomes compared to younger ones. This principle applies not only to solid, assembled organ transplants but also dissociated cells.
Notably, adult stem cells — primitive cells that can mature and replenish certain tissues — transplanted into recipients are capable of developing into cells for multiple tissue types and may contribute to recipient organ and tissue function. These cells, depending on their biological age, exert either rejuvenating or aging effects.
It is unclear whether these transplanted adult stem cells or organs impact recipient cell and tissue function predominantly by acting as a local source of secreted soluble factors, or in fact by integrating into and contributing to target organ function.
The recognition that donor age and recipient age affect organ transplantation outcomes has led to the initiation of programs attempting to allocate organs in a manner that matches donor age and recipient age. This rationale is predominantly based on the superior functions of younger organs compared with older ones. Age-matched transplants may also reduce some of the potential adverse consequences of introducing senescent cells when transplanting old donor organs into young recipients.
Additional benefits may be obtained from treating donors, recipients, or transplanted biospecimens whether cells or an entire organ with therapies that promote rejuvenation or target senescent cells. Transplanting senescent cells into young mice may shorten survival while inducing age-related traits and diseases. Therefore, organ or cell transplantation from old donors harboring senescent cells may induce age-associated dysfunctions in younger recipients.
However, administering drugs that eliminate senescent cells called senolytics at the time of transplanting cells could possibly prevent frailty and improve survival. Even after frailty has already developed, senolytics are still effective, suggesting that it is possible to overcome some of the problems that may accelerate aging-related processes when organs are transplanted from old donors.
For solid organ transplantation, several windows of therapeutic targeting exist, including treatment of the donor, recipient, and graft itself. Treatment of the donor with senolytic agents prior to donation, for example, is one potential means of depleting senescent cells within the graft.
(Lau et al., 2019 | J Clin Invest.) Potential opportunities for therapeutic intervention. Left: Older transplant donors may be treated with senolytic agents before organ donation to a younger recipient. Middle: Treatment of the graft with senolytic agents following organ procurement and prior to transplantation provides additional opportunities to intervene for the administration of senolytics, potentially via the addition of such compounds to organ preservation solutions and perfusates. Right: Transplant recipients can also be treated with senolytics or senomorphics at the time of or subsequently to transplantation.
So, coming back to The Island, which in itself is a Frankenstein-like amalgamation of movie parts (half creepy sci-fi parable and half high-tech action picture), and the question of whether organ transplantation can help us live forever, the answer is most likely “no.” But can it help increase our lifespan, improve our overall health, and prevent disease? Theoretically, “yes.”
And with 3-D printed organs coming soon to a clinic near you, there’s no telling how much of a dent this could make into extending people’s lives. In the meantime, and without an illegal cloning movement, scientists will continue to try to understand the best approach to organ transplantation and aging.