Replacement as the Future of Healthy Aging

Blog Author: Sierra Lore, PhD candidate, Verdin Lab

Sierra Lore

In our Nature Aging perspective, Replacement as an Aging Intervention, we introduce the term ‘replacement interventions’ as a class of therapies aimed at restoring or substituting aged cells, organs, or brain systems. In this paper, we present the first unified framework of replacement for aging, laying out the historical context, evidence and feasibility, and specific approaches. As first author, I had the privilege of constructing this perspective with the world’s leading aging scientists—Eric Verdin, George Church, Vadim Gladyshev, Anthony Atala, Morten Scheibye-Knudsen, and Jesse Poganik.

Biology of aging and longevity science has seen an increase in research, funding, and public interest in recent years. And with good reason—in addition to the emotional distress and physical pain experienced by aging individuals and their loved ones, increasing healthy life expectancy by 1 year is estimated to save $38 trillion. Though scientists have been working on improving healthspan and lifespan since the beginning of medical research, dating back to 1500 BCE, the field of aging was not established until the 20th century. In 1974, the National Institute on Aging was set up by the U.S. federal government under the NIH. 25 years later, the Buck Institute for Research on Aging, the first research institute solely focused on the biology of aging, opened its doors.

Since this surge in aging research, there has been substantial progress in the aging field. We have made new discoveries—cellular senescence, the NAD⁺–sirtuin axis, and organ-specific biomarkers—and gained a deeper understanding of the fundamental mechanisms of aging. However, we have yet to see an intervention that significantly extends lifespan in humans, because aging is not merely a disease of biochemistry. Rather, it is the gradual breakdown of structure and function of cells, tissues, and organs.

By contrast, replacement interventions, such as joint replacements, pacemaker devices, and transplant therapies have a long-standing history of restoring function in humans with injury or disease contexts. The first known prosthetic part dates back to the 15th century BCE, when an Egyptian toe was replaced with wood. The first successful joint replacement (shoulder) took place in 1893, and the first successful solid organ transplantation (kidney) occurred in 1955. We have been successfully using replacement interventions before the field of aging biology was even formally established. However, before this paper, these individual replacement interventions have all been siloed and used as last-resort treatments.

In this Perspective, we unite current disparate replacement advances into a single, field-defining framework of replacement interventions used preventatively for healthy aging. We categorize them into biological replacements (living grafts such as iPSC-derived tissues or genetically engineered organs) and synthetic replacements (mechanical or electronic devices like pacemakers and neural prosthetics). Within each category, we further subdivide by scale—cellular, organ, and brain—highlighting how even the most complex circuits might one day be swapped out or augmented.

Thanks to enabling technologies—induced pluripotent stem cells, CRISPR-mediated immune tuning, organ-specific aging clocks, advanced microfluidics and biomaterials—these therapies have made huge strides in recent years. Today, growing organs in pigs (xenotransplantation) is advancing us toward a new organ supply, brain–machine interfaces are already providing paraplegic individuals with improved mobility, and cancer immunotherapies are helping make previously fatal cancers curable.

We already have the tools to rebuild and rejuvenate the aging body. Now, as a united aging field, we must expand on these existing medical practices used in other medical sectors. The challenge before us is clear: how do we move from proof-of-concept to large-scale practice, in a way that is ethical, affordable, and equitable for everyone?