Cell & Gene Therapies in Longevity: From CRISPR to Cellular Rejuvenation

The translational frontier of geroscience lies in cell and gene therapies, tools capable of directly correcting or reprogramming the molecular defects that drive aging. Advances in precision genome editing, epigenetic reprogramming, and stem cell engineering are rapidly moving from preclinical proof-of-concept to human trials, attracting major biotech investment and positioning this theme as a centerpiece of modern longevity conferences.

Precision Genome Editing: CRISPR and Beyond

CRISPR-Cas9 has evolved into a suite of increasingly refined tools. Base editing (CBE, ABE) and prime editing enable single-nucleotide changes without double-strand breaks, dramatically reducing off-target risks and insertion/deletion mutations. These are now being deployed to correct progeroid syndromes (e.g., Hutchinson–Gilford progeria) and common age-related variants.

Notable 2024–2025 milestones:

• In vivo base editing of PCSK9 and TTR in non-human primates achieving >60% allelic correction and sustained protein knockdown.

• Prime editing efficiency exceeding 50% in primary human hepatocytes, opening doors to permanent correction of APOE4 (Alzheimer’s risk) and other aging-associated alleles.

Longevity-focused companies are targeting klotho upregulation, MYC/Oct4 modulation, and single-gene drivers of senescence (e.g., p16^INK4a^ knockdown) using liver- or CNS-directed AAV delivery.

Epigenetic Reprogramming and Cellular Rejuvenation

Partial reprogramming with transient Yamanaka factors (OSKM) has emerged as the most promising non-mutational approach to reverse aging hallmarks. Key advances:

• In vivo partial reprogramming in mice restores epigenetic age (Horvath clock reversal >50%), vision (optic nerve crush model), and lifespan without teratoma risk when limited to 3–7 days of expression.

• Chemical cocktails (e.g., small-molecule OSK activation) now achieve similar rejuvenation effects without viral vectors, reducing regulatory and safety barriers.

• First human trials (Phase 1/2) of ex vivo T-cell reprogramming for immune rejuvenation began in 2024, with interim data showing restored thymic function markers.

Loss-of-function studies confirm that rejuvenation primarily acts via restoration of youthful DNA methylation patterns and nucleocytoplasmic compartmentalization, not cell replacement.

Stem Cell Therapies and Tissue Restoration

Pluripotent stem cell-derived replacements are entering clinical use:

• Hypoimmunogenic iPSCs (HLA-edited or universal donor lines) for retinal pigment epithelium, dopaminergic neurons, and pancreatic beta cells.

• Paracrine-engineered MSCs secreting klotho, GDF11, or TIMP2 to combat brain and systemic aging.

• Direct in vivo reprogramming (e.g., glia-to-neuron conversion) for Alzheimer’s and spinal injury.

Investment and Translational Landscape (2025)

• $8 billion invested in cell/gene longevity startups since 2022 (AltOS Labs, NewLimit, Shift Bioscience, Retro Biosciences, Turn Bio, Clock.bio, etc.).

• More than 20 INDs cleared for aging-indication cell/gene therapies, including:

  • Allogeneic rejuvenated CAR-Ts with restored CD28 signaling.

  • AAV-delivered telomerase + follistatin for sarcopenia.

  • Prime-edited hematopoietic stem cells targeting p16/p53 senescence pathways.

Challenges and Outlook

Major hurdles remain: durable in vivo delivery to post-mitotic tissues, immune responses to repeated AAV dosing, and defining clinically meaningful endpoints for “aging” as an indication. Yet the convergence of safer editing tools, non-integrating reprogramming methods, and scalable manufacturing has transformed cellular rejuvenation from speculative to near-term clinical reality.

At longevity conferences, this theme now commands the main stage—bridging fundamental aging biology with actionable, investable therapeutics that promise not just lifespan, but genuine reversal of biological age.