One of the most consistent pieces of advice we have received from regulatory consultants and from published FDA guidance documents is this: the agency cannot approve a drug for "aging." Aging is not a disease. It is a biological process, and regulatory frameworks built around the IND-to-BLA pathway require a defined indication with measurable clinical endpoints, a patient population with a clinical condition, and a benefit-risk calculation that regulators can evaluate against existing standard of care. None of those elements exist for "aging" in the abstract.
This is not a bureaucratic obstacle to be cleverly navigated. It is a substantive scientific constraint that forces longevity therapeutics developers — including us — to make a choice early in development that will shape everything that follows: which specific age-related condition does this drug treat, and what does clinical benefit look like for patients with that condition? This post maps the emerging consensus on how that question is being answered across the field, what the regulatory agencies have communicated publicly and through pre-IND processes, and what it means specifically for an mRNA upregulation approach targeting proteins like Klotho and FOXO3.
Why "Aging as a Disease" Is a Regulatory Non-Starter for Now
The "aging as a disease" argument has been made repeatedly in the academic literature and has attracted genuine philosophical interest. The argument holds that the biological processes of aging meet any reasonable definition of a pathological process: they produce measurable dysfunction, they are associated with increased morbidity and mortality, and they are in principle amenable to intervention. Several researchers have proposed that regulatory agencies should create a formal "aging" indication that would allow drugs targeting the aging process to be approved on the basis of healthspan or functional aging biomarkers.
This argument has not moved FDA or EMA in any practical direction, at least not yet. The core regulatory objection is not philosophical but operational: there are no validated clinical endpoints for "aging reversal" or "healthspan extension" that have been accepted by either agency as primary or even secondary endpoints in a pivotal trial. Without an accepted endpoint framework, there is no defined path to approval, and FDA in particular is cautious about creating new approval frameworks without strong scientific consensus on what constitutes clinically meaningful benefit.
FDA did publish a discussion paper on aging biomarkers and their potential use in drug development, and there are active conversations within the agency about how biological age measures might eventually be incorporated into regulatory thinking. But the operative word is "eventually." The practical reality for a company planning an IND in the next two to four years is that the approval path runs through a conventional disease indication, not through a novel aging-specific framework.
The Indication Selection Logic for Longevity-Mechanism Drugs
If the drug must target a recognized disease, the question for a longevity biology program is which recognized diseases are most mechanistically aligned with the targets being developed. For us, this question has a relatively clear answer: the proteins we are pursuing — Klotho and FOXO3, along with several others in our pipeline — have documented associations with neurodegeneration, kidney disease, and metabolic dysfunction. These are established disease areas with existing clinical infrastructure, validated biomarkers, and precedent regulatory pathways.
For Klotho specifically, the published clinical evidence points most strongly toward two indication areas. First, chronic kidney disease (CKD): Klotho is produced primarily by the kidney tubular epithelium, Klotho levels decline with CKD progression, and low Klotho is associated with accelerated cardiovascular and musculoskeletal deterioration in CKD patients. Several academic groups and at least one clinical-stage company have pursued recombinant Klotho protein replacement in CKD, providing some precedent for Klotho as a therapeutic target. Second, cognitive decline and Alzheimer's disease: CSF Klotho levels are reduced in individuals with MCI and Alzheimer's disease compared to age-matched controls, and preclinical work in mouse models has shown cognitive benefit from Klotho supplementation. Both indication areas have established clinical endpoints — eGFR decline rate and serum phosphate for CKD; cognitive test batteries and hippocampal volume measures for the neurodegeneration indication — that would be acceptable in a regulatory submission.
For FOXO3, the indication logic is somewhat different. FOXO3 is a broadly protective transcription factor whose activity is associated with longevity across multiple model organisms and in human centenarian genetics, but its mechanism involves regulating multiple downstream pathways simultaneously. This breadth of activity is biologically interesting but makes indication selection more complex. The clearest near-term clinical context for a FOXO3-upregulating mRNA is probably a specific neurodegenerative condition where oxidative stress, autophagy impairment, and insulin/IGF-1 dysregulation are all mechanistically relevant — Parkinson's disease is a reasonable candidate, as is ALS, though both have challenging clinical trial design considerations.
mRNA-Specific Regulatory Considerations
Beyond indication selection, mRNA therapeutics have a specific set of regulatory considerations that apply regardless of the indication chosen. The regulatory framework for mRNA drugs has developed substantially since the COVID-19 mRNA vaccines, and FDA and EMA have both issued guidance documents that provide clearer expectations than existed even three years ago.
The key regulatory documents include FDA's guidance on chemistry, manufacturing, and controls (CMC) for mRNA products, which establishes expectations for characterizing the mRNA drug substance — sequence identity, capping efficiency, poly-A tail length distribution, dsRNA content, protein impurities from the IVT reaction — and for characterizing the LNP formulation in terms of particle size, encapsulation efficiency, lipid composition, and stability. These requirements are more detailed than many early-stage mRNA programs have prepared for, and we have spent significant time building analytical methods to meet them before we reach the IND stage.
The immunogenicity assessment expectations for mRNA therapeutics are another area where the post-COVID regulatory landscape has sharpened expectations. Because mRNA is inherently immunostimulatory, and because the COVID-19 mRNA vaccine programs generated a large amount of data on mRNA immunogenicity in humans, FDA's expectations for characterizing the innate immune response to novel mRNA therapeutics are more explicit than they would have been before 2021. Modified nucleoside incorporation — particularly N1-methylpseudouridine, which we use — substantially reduces innate immune activation, and the published data supporting this modification is sufficiently robust that it is now essentially standard practice. But the specific immunogenicity package expected in a pre-IND or IND submission still requires characterization of innate immune markers in relevant animal models and, where possible, in ex vivo human PBMC assays.
We are not saying that the regulatory path for mRNA therapeutics is unusually difficult. For the disease indications we are targeting, mRNA is probably no harder to develop than a recombinant protein replacement therapy and easier in some respects than a gene therapy where integration concerns add regulatory complexity. The point is that the regulatory expectations are specific and well-defined, and understanding them early in development avoids expensive late-stage surprises.
Where EMA Diverges From FDA
For an Israel-based company with global ambitions, the EMA pathway matters as much as FDA. EMA's approach to novel therapeutic modalities has some important differences from FDA's approach that affect development planning.
EMA has been somewhat more receptive than FDA to biomarker-based endpoints in early clinical trials, which is relevant for a longevity-biology program where functional biomarkers may be available before hard clinical endpoints are reachable within a reasonable trial duration. The EMA Innovation Task Force and the PRIority Medicines (PRIME) scheme provide early engagement mechanisms that allow companies to discuss regulatory strategy before IND-equivalent (CTA) filing, and we have found the PRIME scheme discussions in our space to be genuinely substantive rather than purely procedural.
EMA has also been developing its thinking on aging biomarkers and geroscience more actively than FDA in some respects — the ESGF (European Geroscience Forum) has had formal dialogue with EMA about frameworks for evaluating aging-related interventions, and while this has not yet produced a formal guidance change, it has influenced how EMA evaluators approach pre-submission meetings on longevity-mechanism therapeutics.
The practical difference for our program is that we are planning our first-in-human strategy to include parallel FDA pre-IND and EMA PRIME consultation, targeting CKD as the lead indication for Klotho. CKD has the advantage of relatively rapid biomarker endpoints (eGFR trajectory over 12-24 months), a patient population with high unmet need, and precedent for biologic protein replacement approaches that provides some regulatory analogy. The neurodegeneration indication — which is ultimately the application we care most about for a longevity program — would be the secondary indication development, building on the safety and pharmacokinetic data generated in CKD.
Biomarker Strategy for a Longevity Biology IND Package
One of the most important decisions in an early longevity therapeutic development program is the biomarker strategy, because biomarkers determine what you can measure in a Phase 1 trial beyond safety, and what you measure in Phase 1 determines your ability to make go/no-go decisions before investing in larger efficacy studies.
For Klotho, the circulating soluble Klotho (s-Klotho) level is the most obvious pharmacodynamic biomarker — if we are delivering mRNA that encodes alpha-Klotho to cells, we expect circulating s-Klotho to increase. This is a relatively clean pharmacodynamic endpoint in that it is directly connected to the mechanism of action, and commercial ELISA assays for s-Klotho are available, though not yet standardized across clinical sites in a way that supports multicenter studies without careful harmonization work. We are investing in reference standard development for s-Klotho measurement as part of our IND-enabling work.
Beyond the direct PD marker, we are tracking a set of downstream markers that reflect Klotho's downstream biology: FGF23 levels (regulated by Klotho), phosphate and calcium homeostasis markers in the CKD context, and — for the neurodegeneration indication — CSF measures of neuroinflammation and oxidative stress markers that are known to be modulated by Klotho signaling in preclinical models. These are not validated surrogate endpoints in a regulatory sense, but they provide biological plausibility data that strengthens the overall IND package and may contribute to Phase 2 endpoint selection discussions.
We are also closely watching the development of DNA methylation biological age clocks — Horvath clock, DunedinPACE, and related measures — as potential secondary endpoints. FDA has not accepted any biological age measure as a drug development endpoint, but the scientific data supporting these measures as integrative indicators of biological aging trajectory is growing, and we believe there is a reasonable probability that one or more of these measures will reach regulatory acceptance within the timeframe of our Phase 2 program. Including them as exploratory endpoints in Phase 1b or Phase 2 at low incremental cost creates an option on a more direct aging readout if the regulatory landscape changes.
What This Means for How We Are Building the Program
The regulatory landscape we have described above has shaped several concrete decisions in how we are structuring our preclinical program. We list them here not as a template but as illustration of how regulatory constraints translate into development strategy at this stage.
First, we selected CKD as the lead indication ahead of the neurodegeneration indication despite the neurodegeneration indication being more central to our scientific hypothesis. The reason is that CKD offers a shorter path to biomarker endpoints, a less technically demanding delivery challenge (kidney parenchyma is more accessible than CNS), and a regulatory analogy from approved protein replacement biologics in CKD that provides some precedent for the mechanism. We intend to run the CKD program in parallel with CNS delivery development rather than sequentially.
Second, we are conducting pre-IND meetings with both FDA and EMA before completing IND-enabling toxicology studies. Pre-IND meetings are non-binding, but they provide critical information about what the agency's current thinking is on analytical expectations, study design requirements, and which aspects of our program are likely to require the most attention during review. The regulatory climate for mRNA therapeutics is evolving quickly enough that waiting until IND submission to learn the agency's current expectations would be costly.
Third, we are building our IND-enabling toxicology package around ICH S9 for the oncology-adjacent CNS indication and ICH S6 for the protein therapeutic analogy, with explicit attention to the immunogenicity assessment guidance. The choice of guideline framework matters because it determines what studies are required and at what stage, and for a small team without unlimited CRO budget, making the right framework choice early is a genuine efficiency decision.
The regulatory path for longevity mRNA therapeutics is navigable. It requires anchoring to specific disease indications with clinical precedent, building a robust CMC and immunogenicity package, and engaging with agencies early rather than optimizing for speed to IND. None of this is fundamentally different from what any thoughtful developer of a novel therapeutic modality would do. What is different is that the longevity biology framing means the scientific rationale for the therapeutic needs more careful translation into regulatory language than it would for a conventional disease-modification story.
