And Sarah Laughed: A Brief Tour of Real Longevity Science

And Sarah laughed within herself, saying, “After I have become worn out, will I have ednah [renewal]?” (Genesis 18:12)

Sarah’s laugh is more than skepticism—it is a question that echoes across millennia. Can aging truly be reversed? Can worn-out tissues regain their youthful vigor? Can biological clocks run backward?

Rashi interprets ednah as the return of menses^[1] and smooth skin^[2]—a biological rejuvenation embedded in the verse itself. The Midrash and Talmud expand on the miracle: Sarah’s reproductive capacity was fully restored, and her body was transformed. This is not merely about childbearing; it is about the fundamental question of whether aging is reversible.

The Science of Turning Back Time

Modern gerontology reveals that aging is not a single switch that flips at a predetermined age. Rather, it is a complex network of interconnected processes—what researchers call the “hallmarks of aging.” These include genomic instability (DNA damage accumulating over time),^[3] epigenetic drift (changes in which genes are active),^[4] cellular senescence (cells that stop dividing but refuse to die),^[5] stem cell exhaustion,^[6] and more.

Here is the revolutionary insight: several of these hallmarks appear to be plastic, not fixed. They can potentially be adjusted, reversed, or reset. Sarah’s question is becoming science’s quest.

Epigenetic Reprogramming: Resetting the Cellular Clock

One of the most promising frontiers involves epigenetic reprogramming—essentially, convincing cells to forget their age. Scientists have discovered that briefly activating a specific combination of factors (called OSKM factors,^[7] named after the genes Oct4, Sox2, Klf4, and c-Myc) can reset molecular age markers in cells.

In landmark experiments, partial expression of these factors in mice not only paused aging, it appeared to reverse it.^[8] Even more remarkably, in studies targeting damaged retinal neurons, a related cocktail (OSK) restored vision and rolled back DNA methylation patterns—one of the key molecular signatures of aging.^[9] The cells became functionally younger.^[10]

Senolytics: Clearing Out the “Zombie” Cells

Another avenue targets what scientists call senescent cells—cells that have stopped dividing but refuse to die. Think of them as cellular “zombies”: they do not perform their normal functions anymore, but they hang around, secreting inflammatory chemicals that damage neighboring tissues. These secretions create what researchers call a “senescence-associated secretory phenotype,” or SASP—essentially, chronic low-grade inflammation that accelerates aging in surrounding areas.

Enter senolytics—drugs designed to selectively eliminate these zombie cells. In mice, removing senescent cells has been shown to delay or even reverse several age-related pathologies. More excitingly, early human trials are showing promise. In patients with severe lung scarring (idiopathic pulmonary fibrosis), a short course of two drugs—dasatinib (originally a cancer medication) and quercetin (a plant-derived compound available as a supplement)—proved safe and was associated with improvements in physical function, including increased walking distance.^[11] While these are preliminary findings, they suggest the principle works in humans, not just mice.

The Landscape of Aging: Valleys, Ridges, and Renewal

To understand what is happening at a deeper level, imagine cells sitting in “attractor basins” on an epigenetic landscape (Waddington landscape)—a metaphor borrowed from developmental biology and physics. Picture a hilly terrain where balls (cells) settle into valleys (stable cell states). Young cells occupy high, well-organized valleys where genes are precisely regulated—low entropy, high coherence.

As we age, cells gradually roll down into lower, noisier valleys. Gene regulation becomes less precise and more chaotic—higher entropy, lower functional coherence. The cell no longer knows exactly what it should be doing.

Epigenetic reprogramming and senolytics aim to push cells back over the ridge, into the younger, more ordered basins. It is about reducing the molecular entropy of aging—restoring the precise gene regulation patterns that define youthful function. This is not fantasy; it is measurable biochemistry.

The Psalm’s Promise

“Who renews your youth like the eagle.” (Psalm 103:5)

The Psalmist’s image of the eagle—a creature that in ancient tradition was thought to renew itself—resonates with what we are discovering. The biblical miracle of Sarah bearing a child at an advanced age may carry an additional layer of meaning: biological rejuvenation is not metaphysically impossible. It is a challenge, an invitation. If Sarah’s aging were reversed, perhaps the mechanisms exist within nature itself, waiting to be understood and engaged. I see it as a permission, indeed, an imperative to develop the science of age reversal.

Brain Aging: A Personal Research Focus

My current work focuses on one critical aspect of aging: brain aging. Specifically, I research how a particular stage of sleep, called “slow-wave sleep,” can reactivate the glymphatic clearing system—the brain’s sophisticated waste-removal network that operates primarily during sleep.

During deep sleep (known as the slow-wave sleep), the glymphatic system gives the brain a thorough cleansing, flushing out amyloid-beta and other misfolded proteins and pathogens that accumulate during waking hours. This nightly maintenance is crucial for keeping a young and healthy brain. When this system functions optimally, it may help prevent or delay the onset of neurodegenerative conditions. Understanding and enhancing this natural renewal process represents another avenue for pushing back against biological aging—this time, protecting the organ that makes us who we are.

From Miracle to Medicine: What This Means Now

Full-body age reversal is not yet here—we are not about to see 90-year-olds transform into 30-year-olds anytime soon. However, targeted rejuvenation is transitioning from science fiction to legitimate research. We are at the beginning of a profound shift in how we understand aging: not as an inexorable decline, but as a potentially modifiable process.

For now, the most effective interventions remain decidedly unglamorous but powerfully proven: plentiful, high-quality sleep, both aerobic and resistance training, a healthy diet, and maintaining cardiovascular and metabolic health. These are not just “wellness tips”—they are the foundation that allows our cellular repair systems to function optimally. Meanwhile, we must cautiously and rigorously translate epigenetic and senolytic therapies through clinical trials, ensuring they are safe and effective before widespread use.

Between miracle and medicine lies our mandate: to study, to understand, to heal, to cultivate life’s renewal and extension. Sarah’s laugh—born of disbelief—transformed into Isaac’s birth (Isaac, in Heb. Yitzchak, means “he will laugh.”) Isaac was the paragon of modern longevity—he lived to be 180 years old. The Lubavitcher Rebbe once said that Isaac is our father, and we can all potentially live to be 180 years young, as he did—Amen to that!’ Perhaps our own skepticism about conquering aging will likewise transform into joy as science uncovers the mechanisms of rejuvenation.

A longer healthspan is not beyond the horizon. And while we work toward it, we can honor the deeper wisdom: to live fully and meaningfully now, to make every moment count. That itself is a form of renewal and life extension—one available to us today.

[1] Gen. Rabbah 48:17.

[2] Heb. “smooth flesh,” עֶדְנָה, is cognate with an expression of time, עִדָּן, interpreted as a period. Tan. Shoftim 18.

[3] Genomic instability in aging refers to an increased tendency to acquire genetic alterations of various kinds, resulting from increased DNA damage and less-than-perfect replication/repair, and mitotic control. It includes, but isn’t limited to: single-nucleotide variants and small indels that accumulate with age in many tissues, chromosomal/structural lesions, replication stress–driven damage, and mitochondrial genome instability. Mechanistically, this hallmark reflects both more damage (endogenous ROS, mobile elements, replication errors) and less faithful upkeep (age-impaired DNA repair/checkpoints). It’s one of the canonical hallmarks of aging.

[4] Simply put, epigenetic drift is the age-related, partly random “blurring” of the epigenome, which makes gene regulation less precise as we age. More precisely, epigenetic drift refers to the gradual, mostly stochastic change in epigenetic marks—especially DNA methylation—across cells and over time, resulting in increased variability and “noisier” gene regulation with age. Global patterns tend to lose methylation at repeats, while some promoter CpG islands gain methylation; histone marks and chromatin accessibility also shift. Together, these changes make epigenetic states more heterogeneous within a tissue. Classic twin studies show young monozygotic twins are epigenetically similar, but older twins diverge markedly—textbook evidence of age-related drift. Longitudinal twin work confirms divergence over a decade. Imperfect maintenance of methylation during DNA replication, plus environmental/exposure effects, introduces small errors that accumulate, creating epigenetic mosaicism. Drift is linked to dysregulated transcription, stem cell exhaustion, immunosenescence, and increased cancer risk, as clones with advantageous (but aberrant) characteristics expand. It is one pillar of the broader hallmark epigenetic alterations in aging.

[5] Aging of cells. Most senescent cells die through apoptosis—self-destruction, or cellular suicide. If senescent cells don’t self-destruct, they become toxic. With aging, the number of senescent cells increases, which contributes to inflammation—one of the primary causes of aging.

[6] Stem-cell exhaustion is an age-related decline in both the number and function of tissue stem cells, characterized by reduced self-renewal, impaired differentiation, and increased senescence. It is driven by accumulated damage, epigenetic alterations, telomere attrition, mitochondrial and niche/inflammatory changes—yielding poorer maintenance and repair of tissues.

[7] OSK and OSKM are sets of Yamanaka factors—transcription factors used to reprogram cells. They bind regulatory DNA, remodel chromatin, and reset epigenetic programs toward pluripotency. In longevity work, OSK (without c-Myc) is often used for partial or transient reprogramming to reduce tumor risk and avoid full loss of cell identity, whereas OSKM reprograms more aggressively but carries higher oncogenic/teratoma risk due to c-Myc.

[8] Ocampo, A., Reddy, P., Martinez-Redondo, P., et al. (2016). “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.” Cell, 167(7):1719-1733.e12. doi: 10.1016/j.cell.2016.11.052.

[9] Lu, Y., et al (2020). “Reprogramming to recover youthful epigenetic information and restore vision.” Nature, 588(7836):124-129. doi: 10.1038/s41586-020-2975-4.

[10] Karg, M.M., Lu, Y.R., Refaian, N., Cameron, J., Hoffmann, E., et al. (2023). “Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma.” Cellular Reprogramming, 25(5):188-200. doi: 10.1089/cell.2023.0074.

[11] Baker, D., Wijshake, T., Tchkonia, T. et al. Clearance of p16^Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). https://doi.org/10.1038/nature10600