Malav Trivedi and I were wondering how long it might take to find bioengineering solutions that can reverse aging enough to keep people from aging to death. Below is our sketch of one possible timeline we worked out for the Longevity Biotech Fellowship.

Authors: Kris Borer, Malav Trivedi

Bioengineering holds great potential for improving the human condition through genetic and epigenetic reprogramming. It is plausible that bioengineering will one day allow humans to modify their biochemistry to the point that diseases and death due to aging no longer occur.

However, even if bioengineering will eventually be a complete solution to the problem of aging, it is not clear how much time and attention the longevity community should spend on it. If we want to save as many lives as possible, we need to allocate every minute to the highest impact projects. Given the enormous efforts already going into bioengineering from the rest of the biotech community, the longevity community might be more effective by focusing bioengineering efforts on opportunities in the fields of biostasis and replacement.

To understand the costs and benefits of different ways of pursuing longevity within the realm of bioengineering, we need to have a viewpoint on the roadmap and timeline for a bioengineering-based solution to aging, as well as the impact that bioengineering could have on the biostasis and replacement. Each of these are areas of speculation, but educated guesses could help divert resources to projects that otherwise would have been undervalued and underdeveloped.

A potential path for bioengineering radical life extension

In order to solve aging with bioengineering, we would need several technological developments:

1. A way to safely deliver successive therapies throughout the body.
2. A way to control where therapies are activated, either by selective delivery or selective activation.
3. Therapies that can overcome age-related changes to cells.
4. Therapies that can overcome age-related changes to the extracellular matrix.

1. Systemic, Safe, and Efficient Therapeutic Delivery

To counteract age-related degeneration across tissues, therapeutics must be uniformly distributed and delivered safely to the entire organism. Current vectors such as lipid nanoparticles and adeno-associated viral vectors (AAVs) have shown promise in specific contexts but face challenges for whole-organism rejuvenation.

• Development of Advanced Vector Systems– Cutting-edge research is exploring fusion-associated small transmembrane proteins, cellular vesicles, and hybrid nanoparticle-based systems as next-generation delivery vectors. Fusion-associated proteins, for example, facilitate cellular uptake by mimicking viral entry pathways, which could be harnessed to bypass tissue barriers like the blood-brain barrier (BBB).
• Targeting and Homing Mechanisms– Efficient systemic delivery requires vectors that recognize and selectively bind specific cell surface markers. Advances in receptor-mediated endocytosis, ligand-based targeting, and biomarker-sensitive nano-ligands are under investigation to achieve cell-specific targeting across diverse tissue types. For instance, nanoparticles coated with ligands targeting senescent cell surface proteins may enable selective intervention in aged tissues, enhancing therapeutic safety by minimizing off-target effects.

With aggressive R&D in this area, it is conceivable that an efficient, safe, and widely applicable delivery mechanism could be developed within the next 10 years, providing a fundamental tool for age-targeted therapies.

2. Precision Control of Therapeutic Activation

Delivering therapies is only the first challenge; ensuring that they activate precisely where needed and under appropriate conditions is critical. Uncontrolled expression or activation of therapeutic agents can induce unintended side effects and compromise efficacy.

• Cell-Type and Context-Specific Activation– Current strategies focus on engineering vectors or proteins that respond to local transcriptional profiles. One approach uses CRISPR-based synthetic transcriptional regulators activated only under specific epigenetic conditions, such as the presence of aging markers like CDKN2A/p16INK4a. Conditional promoters and inducible gene circuits sensitive to cellular damage markers (e.g., oxidized lipid byproducts) could further refine this approach.
• Temporal Control via External Stimuli– Techniques such as optogenetics and chemogenetics offer potential for temporal control of gene expression. For example, light-activated ion channels can trigger expression cascades in specific cell populations, while drugs or small molecules could initiate therapeutic protein expression on demand.

Controlled activation with these advanced approaches may be achievable within a decade, allowing for highly specific therapeutic interventions that reduce collateral cellular stress and enable long-term, targeted rejuvenation treatments.

3. Mitigating Age-Related Cellular Damage

Even with delivery under control, the prospects for overcoming age-related changes to cells using bioengineering is quite poor. Anything in a cell can be damaged. Cells in vitro can escape from this problem by diluting damage through cell division, but it would be challenging to make use of this mechanism in an adult body. This is especially true in the brain.

Cellular aging is driven by the accumulation of molecular damage, including DNA mutations, epigenetic drift, lipofuscin, mitochondrial dysfunction, and proteostasis collapse. Addressing these requires interventions capable of restoring or bypassing damaged intracellular systems.

• Targeted Damage Mitigation and Organelle Repair– Future therapies may use mitophagy and autophagy-enhancing drugs to recycle damaged organelles. Additionally, strategies for non-homologous recombination repair or enzyme-based DNA repair could address accumulated mutations and ensure genomic integrity.
• Enhanced Cell Cycle Manipulation– In non-proliferative cells (e.g., neurons), where damage accumulates without dilution, novel methods are required to clear cellular damage. Bioengineered autophagy inducers could selectively target and degrade damaged macromolecules, while induced cell cycle re-entry, similar to induced pluripotency, may help aged cells reset without transitioning to full dedifferentiation.
• Genome-Wide Maintenance Systems– Synthetic biology holds potential for developing genomic maintenance systems—engineered repair enzymes, for instance, that could constantly scan and correct mutations or repair epigenetic drift across the genome.

Addressing intracellular damage and genomic stability represents a formidable challenge, and realistic progress toward a comprehensive solution may require 25 years of research and development, including extensive safety testing for human application. If you think this is pessimistic, consider that one small part of this body of work is curing cancer.

4. Repairing and Rejuvenating the Extracellular Matrix (ECM)

The ECM, comprising collagen, elastin, proteoglycans, and glycoproteins, underpins tissue structure and function, and its degradation significantly impacts cellular health. Unlike cells, which are capable of internal repair, the ECM lacks an inherent regenerative mechanism, making its rejuvenation particularly challenging.

• Cross-Link Reduction and Matrix Remodeling– Cross-linking of ECM proteins, such as collagen, increases with age, leading to reduced elasticity and altered mechanical properties of tissues. Advanced glycation end-product (AGE) breakers and novel cross-link cleaving enzymes could be developed to selectively remove or prevent ECM cross-linking.
• Bioactive ECM Scaffolding and Matrix Regeneration- Bioengineering scaffolds that mimic youthful ECM could be seeded with bioactive molecules to stimulate native cells to repopulate and remodel damaged ECM. These scaffolds could include matrix metalloproteinases (MMPs) to aid in clearing degraded components and proteoglycans that bind growth factors, encouraging cellular repopulation and ECM deposition.
• Signal Modulation to Enhance Cellular Function– The ECM transmits biochemical cues that regulate cell behavior and function. As ECM quality declines, cells receive aberrant signals that promote aging phenotypes. Engineered ECM that mimics youthful signaling could help cells maintain functionality, bypassing the influence of the aged ECM and potentially extending tissue function longevity

Even with cellular damage under control, the prospects for overcoming age-related changes to the extracellular matrix are even less promising. Whereas cells have direct control of their internal environment, they only have indirect control of their external environment. It’s one thing to build a helicopter. It’s quite another thing to rebuild it while it is in the air. To make matters worse, the ECM has strong control over cells and the more damaged the ECM, the more work it will take to make cells behave properly. Perhaps the cells could be made to ignore confusing signals from the ECM without disrupting their essential functions related to the ECM. Yet, even if you have perfect cells, aging ECM will still kill you as the mechanical properties of tissues drift away from what is needed to function properly and sustain life. The challenge of repairing ECM is an order of magnitude harder than repairing cells, but let’s say it is merely twice as hard and might be done in 50 years.

That’s a somewhat hopeful scenario for students, but what about everyone dying in the meantime?

How bioengineering can help biostasis.

If bioengineering won’t solve aging on its own anytime soon, is there a more effective use of the technology? One potential path is to use bioengineering to accelerate progress in biostasis. Potential accelerants include:

1. Cellular and tissue modifications to mitigate damage during vitrification and revival.
2. Therapies to mitigate cryoprotectant toxicity.
3. Controllable endogenous cryoprotectant production.
4. Technology to produce cross-linking.
5. Technology to reverse cross-linking.

Many of these projects could be solved much faster and cheaper than work required for a bioengineering solution to aging. Not only would there be a lower cost per life saved, but you would save any lives that would otherwise be lost while waiting for bioengineering therapies to become available.

How bioengineering can help replacement.

Bioengineering can also provide assistance to the replacement strategy for longevity. Potential accelerants include:

1. Techniques for brainless cloning.
2. Techniques that aid in brainless clone gestation.
3. Techniques that make clone maintenance easier.
4. Techniques for accelerated growth of brainless clones.
5. Modifications that simplify body transplant surgery.
6. Modifications that improve body transplant survival.
7. Modifications that improve functional recovery after transplantation.

Bioengineering is essential to the long-term success of the replacement strategy. It is essential that we develop a scalable source of donor tissues, organs, and bodies. Big gains would also be expected by shifting bioengineering from the hard problem of aging to the relatively easy problem of transplantation optimization. It is much easier to make improvements to survival and functional recovery of a surgery than to solve the myriad of age-related damage. Like cryonics, efforts focused here have the potential to save lives that would be lost otherwise.

A possible path forward.

In the near term, bioengineering will likely produce therapies that increase healthspan, which will help some people avoid the need for cryonics. For those who depend on cryonics for their survival, bioengineering can provide therapies that improve their odds of survival.

For those who get to attempt replacement before cryonics, bioengineering will provide therapies that improve their odds of radically extending their life with a young body. Bioengineering will then provide them with a means of repairing their brain tissue and avoiding routine brain surgery. 

Eventually, the concentration of bioengineering efforts on the brain, in combination with the support of young bodies, will allow some to achieve longevity escape velocity. These fortunate people will get to enjoy a bioengineering solution to aging. Getting as many people there as possible requires a rational allocation of time and money to the highest impact projects. For those working in bioengineering, those projects may be in cryonics and replacement.