Kenyon Targets Hormone Receptors to Double Lifespan and Stall Disease

Cynthia Kenyon: Experiments that hint of longer lives — TED

TED

Suppressing conserved insulin and IGF-1 signaling unleashes cellular repair networks via FOXO, proving that aging is genetically regulated and that single drug therapies can prevent multiple age-related diseases simultaneously.

AI-assisted summary of Cynthia Kenyon: Experiments that hint of longer lives — original source. Check the original for full context.

Source published: 2011-11-17

Key ideas

A single genetic mutation in the daf-2 hormone receptor doubles the lifespan of C. elegans roundworms, keeping them active, fertile, and biologically youthful for twice as long as normal worms. (1:09)
The daf-2 receptor corresponds to human insulin and IGF-1 receptors, revealing an evolutionary conserved pathway across worms, flies, and mammals where down-regulating hormone signaling promotes longevity. (3:41)
Studies of human centenarians show an increased prevalence of mutations in the IGF-1 receptor gene and specific FOXO variants, confirming the pathway's relevance to human life expectancy. (5:52)
Longevity therapeutics aim to pharmacologically inhibit nutrient-sensing pathways like TOR or activate FOXO repair mechanisms to broadly protect against age-related chronic illnesses without permanent genetic alteration. (11:16)

Detailed notes

## Background This talk was delivered by biochemist Cynthia Kenyon and published on YouTube by TED on November 17, 2011. According to the video description, Kenyon discusses her discovery of a simple genetic mutation that can double the lifespan of the roundworm C. elegans, exploring how lessons from this research could eventually help significantly extend youthful human life.

## TL;DR Cynthia Kenyon challenges the traditional biological view that aging is merely inevitable wear and tear, demonstrating that lifespan is fundamentally regulated by genes. By mutating the daf-2 hormone receptor in microscopic C. elegans roundworms, her lab doubled their lifespan while keeping them youthful and active, an effect mediated by the FOXO transcription factor activating extensive cellular repair and defense programs. Kenyon shows that this ancient insulin/IGF-1 signaling pathway is conserved across flies, mice, and humans, with natural receptor and FOXO variants appearing frequently in human centenarians. Rather than pursuing germline genetic editing, her work focuses on developing reversible small-molecule therapeutics—such as inhibitors of nutrient-sensing pathways like TOR—to delay multiple age-related chronic illnesses simultaneously and extend healthy youthspan.

## Atmosphere & style The presentation carries an optimistic, intellectually exhilarating tone, blending rigorous molecular genetics with accessible, witty analogies like elderly worms 'going skiing' or cellular repair crews answering a building superintendent's call. Kenyon speaks with clear, accessible authority and infectiously youthful curiosity, drawing the audience into what once felt like science fiction before transitioning to a thoughtful, grounded Q&A with Matt Ridley. Watching the talk feels both eye-opening and reassuring, as complex biochemical pathways are revealed not as immutable barriers, but as evolutionary dials that human medicine might one day calibrate.

## Bulletin - [01:09](https://www.youtube.com/watch?v=V48M5j-6zdE&t=69s) A single genetic mutation in the daf-2 hormone receptor doubles the lifespan of C. elegans roundworms, keeping them active, fertile, and biologically youthful for twice as long as normal worms. - [03:41](https://www.youtube.com/watch?v=V48M5j-6zdE&t=221s) The daf-2 receptor corresponds to human insulin and IGF-1 receptors, revealing an evolutionary conserved pathway across worms, flies, and mammals where down-regulating hormone signaling promotes longevity. - [05:52](https://www.youtube.com/watch?v=V48M5j-6zdE&t=352s) Studies of human centenarians show an increased prevalence of mutations in the IGF-1 receptor gene and specific FOXO variants, confirming the pathway's relevance to human life expectancy. - [11:16](https://www.youtube.com/watch?v=V48M5j-6zdE&t=676s) Longevity therapeutics aim to pharmacologically inhibit nutrient-sensing pathways like TOR or activate FOXO repair mechanisms to broadly protect against age-related chronic illnesses without permanent genetic alteration.

## Key takeaways - [00:15](https://www.youtube.com/watch?v=V48M5j-6zdE&t=15s) Lifespan variation across different animal species demonstrates that aging is genetically regulated rather than an unalterable, passive wearing down like an old shoe. - [01:09](https://www.youtube.com/watch?v=V48M5j-6zdE&t=69s) Mutating the daf-2 gene in C. elegans doubles their lifespan from one month to two months without diminishing fertility or youthful vitality. - [03:41](https://www.youtube.com/watch?v=V48M5j-6zdE&t=221s) The daf-2 gene encodes a transmembrane hormone receptor homologous to human insulin and IGF-1 receptors, showing that normal signaling actively accelerates aging. - [05:52](https://www.youtube.com/watch?v=V48M5j-6zdE&t=352s) Mutations that slow down aging in model organisms confer broad resistance against age-related conditions, including cancer, Alzheimer's disease, and cardiovascular disease. - [05:52](https://www.youtube.com/watch?v=V48M5j-6zdE&t=352s) Centenarians in an Ashkenazi Jewish cohort show a significantly higher rate of mutations that dampen IGF-1 receptor function, mirroring the genetics of long-lived mutant worms. - [07:13](https://www.youtube.com/watch?v=V48M5j-6zdE&t=433s) When daf-2 signaling is reduced, the FOXO transcription factor enters the nucleus to activate an extensive suite of protective genes, including antioxidants, DNA repair enzymes, chaperones, and immune factors. - [07:13](https://www.youtube.com/watch?v=V48M5j-6zdE&t=433s) Animals possess an innate, latent capacity for extended survival evolved to protect against starvation and harsh conditions, which is triggered constitutively by daf-2 mutations. - [09:44](https://www.youtube.com/watch?v=V48M5j-6zdE&t=584s) FOXO operates like an apartment building superintendent coordinating specialized repair crews, and specific FOXO variants are globally associated with exceptional human longevity. - [11:16](https://www.youtube.com/watch?v=V48M5j-6zdE&t=676s) Inhibiting the nutrient sensor TOR with the drug rapamycin extends lifespan in mice even when administered late in life, though its immunosuppressive properties highlight the need for safer small-molecule alternatives. - [13:00](https://www.youtube.com/watch?v=V48M5j-6zdE&t=780s) Longevity medicine focuses on reversible pharmacological modulation rather than human germline engineering, as completely disabling vital metabolic genes causes severe illness. - [14:19](https://www.youtube.com/watch?v=V48M5j-6zdE&t=859s) Species exhibiting negligible senescence, such as Blanding's turtles, maintain cellular resilience against heat and oxidative stress without displaying physical or reproductive decline as they age. - [14:19](https://www.youtube.com/watch?v=V48M5j-6zdE&t=859s) The ultimate objective of aging research is not merely postponing mortality, but extending the healthy youthspan of human beings.

## Detailed walkthrough ### [00:15](https://www.youtube.com/watch?v=V48M5j-6zdE&t=15s) The Genetic Theory of Aging: Beyond the "Old Shoe"

For generations, humanity has dreamed of delaying the aging process and staying youthful, but traditional biology dismissed the possibility as wishful thinking. Scientists long assumed that aging was merely the inevitable wearing down of living tissues through physical wear and tear, viewing an aging organism as fundamentally no different from an old shoe that gradually falls apart. Cynthia Kenyon challenged this prevailing dogma by looking at the diversity of the natural world: different animal species have drastically different lifespans. Because the differences between species are encoded in their DNA, this observation implies that lifespan and the rate of aging must ultimately be controlled by genes.

Kenyon reasoned that if specific genes govern how quickly organisms age, changing one of those genes in a controlled laboratory experiment might slow down the process and extend healthy lifespan. Identifying such an aging gene would demonstrate that the rate of senescent decline is not a fixed physical constant, raising the prospect that science could eventually intervene in the aging process.

- Scientists historically viewed aging as an inevitable, passive wearing-out process comparable to an old shoe. - Interspecies lifespan differences indicate that aging is genetically regulated. - Cynthia Kenyon summarizes the historic consensus and her hypothesis: “They thought you just wear out, there's nothing you can do about it -- kind of like an old shoe.” She then poses the experimental logic: “So if there are genes like that, then you can imagine that, if you could change one of the genes in an experiment, an aging gene, maybe you could slow down aging and extend lifespan.”

---

[01:09](https://www.youtube.com/watch?v=V48M5j-6zdE&t=69s) The C. elegans Discovery: Halting Aging with daf-2

To hunt for genes controlling aging, Kenyon turned to *Caenorhabditis elegans*, a microscopic roundworm about the size of a printed comma. Due to their naturally brief lifespan—normal worms die of old age after roughly a month—they provide an ideal model organism for aging research. Encouraged by an earlier report of a long-lived mutant, Kenyon’s lab began randomly mutating genes in search of strains that outlived the norm. They discovered that mutating a single gene out of the worm's 20,000 genes—a gene called *daf-2*—doubled the animal's lifespan. While normal control worms were entirely dead by the end of one month, the *daf-2* mutants remained predominantly alive, surviving up to twice as long.

```mermaid flowchart TD accTitle: Impact of daf-2 Mutation on Worm Lifespan accDescr: Comparison of wild-type C. elegans aging versus daf-2 mutant worms over time. subgraph WT["Normal Worm (Wild-Type)"] W1["Young Adult (Active)"] --> W2["2 Weeks: Nursing Home Stage"] W2 --> W3["1 Month: 100% Dead"] end subgraph MT["daf-2 Mutant"] M1["Young Adult (Normal & Fertile)"] --> M2["2 Weeks: Healthy & Going Skiing"] M2 --> M3["2 Months: Lifespan Doubled"] end ```

Kenyon illustrates this difference with video recordings of the worms. In young adulthood (what Kenyon calls their "college student age"), normal worms and *daf-2* mutants look identical: both are lively, active, and fully fertile, laying the same number of progeny. However, after just two weeks, the normal worms exhibit severe senescent decline: their tissues deteriorate, their bodies lie limp and motionless, and only their heads twitch faintly. Even viewers who have never seen a nematode instantly recognize that the animal is decrepit, pointing to a universal physical quality of aging. By contrast, the two-week-old *daf-2* mutant moves vigorously across the plate; it is not in a nursing home, but rather "going skiing." It ages at half the normal speed, taking two full days to accumulate the deterioration a normal worm suffers in one day. Kenyon draws an analogy: it is like a bachelor in his thirties dating a woman who looks his age, only for her to reveal over dinner that she is sixty.

- A normal *C. elegans* lives for about one month; the *daf-2* mutant lives for approximately two months. - The mutation alters only one single gene out of roughly 20,000, leaving fertility and youthful vitality intact. - Highlighting the dramatic contrast at two weeks, Kenyon quips: “It's the same age, but it's not in the nursing home; it's going skiing.” - Kenyon explains the rate of physical decline: “It takes this worm two days to age as much as the normal worm ages in one day.”

---

[03:41](https://www.youtube.com/watch?v=V48M5j-6zdE&t=221s) The daf-2 Receptor: An Ancient Insulin-like Signaling Pathway

The *daf-2* gene encodes a hormone receptor embedded in the cell membrane. Structurally, Kenyon likens the receptor to a baseball glove: its extracellular portion catches circulating signaling molecules, while its intracellular segment relays instructions into the cell. Because mutating and damaging *daf-2* doubles the organism's lifespan, the receptor's normal function in unmutated animals is actively to accelerate the aging process. Kenyon observes that the animal effectively carries its own internal "grim reaper" speeding up senescence.

This receptor is homologous to human receptors for insulin and insulin-like growth factor 1 (IGF-1). While insulin has long been recognized for managing nutrient uptake after feeding and IGF-1 for stimulating tissue growth, Kenyon’s work revealed a third, previously unrecognized function: the regulation of lifespan. When researchers mutated the equivalent hormone pathways in fruit flies and mice, those animals also lived significantly longer. Because the insulin/IGF-1 pathway is conserved across flies, mammals, and nematodes, it represents an ancient evolutionary system that arose in a common ancestor and likely operates similarly in humans.

- The *daf-2* receptor sits across the cell membrane, catching hormones externally and signaling internally. - Disrupting *daf-2* signaling slows down aging, proving that the wild-type pathway normally promotes aging. - The pathway is conserved from worms to flies, mice, and humans. - Kenyon identifies the receptor's wild-type role: “So that means that the normal function of this hormone receptor is to speed up aging.” - She emphasizes the unexpected nature of this internal mechanism: “It's like the animal has the grim reaper inside of itself, speeding up aging.”

---

[05:52](https://www.youtube.com/watch?v=V48M5j-6zdE&t=352s) Centenarians, Disease Resistance, and the All-in-One Approach

Evidence that this hormone system regulates human longevity comes from clinical genetic research. Kenyon highlights a study conducted on a cohort of Ashkenazi Jews in New York City. While most individuals in that population lived to typical life expectancies of 70 or 80, centenarians living to 90 or 100 were significantly more likely to carry natural mutations in the gene encoding their IGF-1 receptor. Just as in the *C. elegans* mutants, these genetic variants reduced the receptor's activity, directly linking reduced hormone receptor signaling to extreme human longevity.

Crucially, delaying aging through this mechanism does not simply extend frailty; it protects against age-related pathology. In mammals and model organisms, advancing age is the primary risk factor for cancer, Alzheimer's disease, and cardiovascular illness. The long-lived mutants exhibit robust resistance across the board: they rarely contract cancer, and when tumors do occur, they are far less severe. Because the animals remain biologically younger for longer, they stay protected against conditions that only afflict old tissues. Kenyon argues that developing drugs or therapeutics that mimic these receptor changes could yield a single intervention capable of treating or preventing multiple age-related chronic diseases simultaneously.

- Centenarians in an Ashkenazi Jewish cohort in New York showed an increased prevalence of loss-of-function mutations in the IGF-1 receptor gene. - *daf-2* and insulin/IGF-1 pathway mutants exhibit striking resistance to cancer, Alzheimer's, and heart disease. - Kenyon outlines the therapeutic potential: “So it suggests that, if we could have a therapeutic or a pill to take to replicate some of these effects in humans, maybe we would have a way of combating lots of different age-related diseases all at once.”

---

[07:13](https://www.youtube.com/watch?v=V48M5j-6zdE&t=433s) The Cellular Mechanism: FOXO and the Stress Survival Program

To understand how a single cell-surface hormone receptor dictates the overall rate of aging, Kenyon’s laboratory mapped the downstream molecular cascade. In a *daf-2* mutant with an impaired receptor, a key gene regulator protein known as FOXO is liberated. Instead of being sequestered, FOXO translocates into the cell nucleus, binds to genomic DNA, and activates a large suite of protective and maintenance genes. These include:

- Antioxidant genes that neutralize oxidative stress. - "Caregiver genes" (molecular chaperones) whose protein products assist other proteins in folding and functioning properly, or escort misfolded proteins to cellular recycling systems. - DNA repair enzymes that fix genetic damage. - Immune defense genes that bolster resistance to pathogens.

```mermaid flowchart TD accTitle: FOXO Signaling Under Normal vs Stress/Mutant Conditions accDescr: Diagram showing how active daf-2 blocks FOXO while mutant or low hormone conditions permit FOXO nuclear entry to induce repair genes. subgraph Normal["Normal Abundant State"] H1["High Insulin / IGF-1"] --> R1["Active daf-2 Receptor"] R1 --> B1["FOXO Blocked from Nucleus"] B1 --> G1["Standard Growth & Nutrient Uptake"] end subgraph Longevity["daf-2 Mutant or Stress State"] H2["Low Hormone / Damaged Receptor"] --> R2["Inactive daf-2 Pathway"] R2 --> F2["FOXO Enters Nucleus"] F2 --> D2["FOXO Binds DNA"] D2 --> T2["Upregulates Antioxidants, Caregivers, DNA Repair & Immunity"] T2 --> L2["Cellular Protection & Doubled Lifespan"] end ```

In normal worms living under optimal conditions, high levels of insulin and IGF-1 hormones stimulate the *daf-2* receptor, which triggers a signaling cascade that keeps FOXO locked out of the nucleus, preventing these protective genes from turning on. Kenyon explains that the insulin/IGF-1 system evolved to signal "good times," prioritizing growth, nutrient absorption, and reproduction when food is plentiful. Conversely, under conditions of harsh environmental stress or famine, hormone levels drop, sending a danger signal throughout the body. The cell responds by sending FOXO into the nucleus to activate its defensive battery, repairing damage and keeping the animal alive until conditions improve. Kenyon points out that animals naturally carry an unexploited, latent biological capacity for extended survival, which is accidentally switched on permanently by the *daf-2* mutation.

- In wild-type conditions, *daf-2* receptor signaling prevents FOXO from entering the nucleus. - In *daf-2* mutants, FOXO enters the nucleus and upregulates antioxidant, chaperone (caregiver), DNA repair, and immune genes. - Kenyon summarizes the hidden resilience within animal biology: “These animals have within them the latent capacity to live much longer than they normally do.”

[09:44](https://www.youtube.com/watch?v=V48M5j-6zdE&t=584s) The Building Superintendent Analogy and FOXO Gene Variations

Cynthia Kenyon illustrates how the FOXO transcription factor functions inside the cell by comparing it to an apartment building superintendent. While the superintendent might ordinarily be a bit lazy—letting the property slowly deteriorate while merely keeping an eye on things—everything changes the moment news arrives that a hurricane is approaching. Rather than boarding up windows or patching the roof personally, the superintendent picks up the phone and calls in reinforcements: the roofer, the window specialist, the painter, and the flooring contractor. In the exact same way, FOXO moves to the DNA to activate a suite of protective genes. When the storm passes, the building is in far better condition than it would have been under normal conditions, and as a result, it lasts significantly longer even when there is no storm at all. This cellular fortification mechanism explains the fundamental biology of life extension.

```mermaid flowchart TD accTitle: FOXO Cellular Fortification Model accDescr: Diagram illustrating how the FOXO transcription factor acts like a superintendent dispatching repair teams to fortify cellular health.

subgraph Trigger ["Environmental Signal"] A["Stress / Reduced Nutrient Signaling"] end

subgraph Activation ["Superintendent Analogy"] B["FOXO Moves to DNA<br/>('Picks Up the Phone')"] C["Mobilizes Repair Subsystems<br/>(Roofers, Window, Floor Crews)"] end

subgraph Outcome ["System Fortification"] D["Enhanced Cellular Protection<br/>& Stress Resistance"] E["Extended Youthspan & Longevity<br/>(Even Without Severe Stress)"] end

A --> B B --> C C --> D D --> E ```

Kenyon points out that although all humans possess FOXO genes, individuals do not all inherit identical variants, just as people inherit different eye colors like blue or brown. Researchers studying long-lived human populations across the globe have discovered that specific forms of the FOXO gene appear significantly more often in centenarians and people living past 90 years of age. While the exact downstream mechanisms in humans remain under investigation, the statistical link across worldwide studies proves that natural variations in FOXO directly influence human life expectancy. Emphasizing the promise of this link, Kenyon states: “And that means that, maybe if we tweak it a little bit, we can increase the health and longevity of people.”

- Population mapping shows that FOXO variants correlate with longevity across diverse ethnic cohorts worldwide. - FOXO acts as a central genetic coordinator rather than carrying out direct repairs itself, transcribing a wide network of protective maintenance genes.

---

[11:16](https://www.youtube.com/watch?v=V48M5j-6zdE&t=676s) Translating Longevity Pathways to Drugs: TOR and Rapamycin

Spurred by discovering that a gene identified in microscopic roundworms also influences human lifespan, Kenyon’s laboratory has moved to working with human cell cultures to design small molecules that can activate FOXO without relying on disruptive genetic alterations. The goal is to produce pharmacological therapies that postpone aging and mitigate age-related chronic illnesses. Kenyon expresses deep optimism about this approach, noting that several proteins governing the aging process have already been mapped.

Among these targets is the nutrient-sensing kinase known as TOR (target of rapamycin), which functions alongside the insulin/IGF-1 signaling pathway. Disruptions to the TOR gene lengthen the lifespan of worms, fruit flies, and mice, mirroring the lifespan extensions achieved through *daf-2* mutations. Crucially, a pharmacological inhibitor for this protein already exists: the drug rapamycin. Administering rapamycin to mice—even late in their lives, at an age roughly equivalent to a 60-year-old human—successfully lengthens their lifespan.

While Kenyon cautions the audience against self-administering rapamycin because it functions as an immunosuppressant used clinically to block organ transplant rejection, the proof of principle is monumental. As Kenyon observes: “So I'm really optimistic, and I think it won't be too long, I hope, before this age-old dream begins to come true.”

- TOR acts as a cellular nutrient sensor whose down-regulation mimics dietary restriction or *daf-2* mutations. - Rapamycin directly binds and inhibits TOR, extending survival when delivered late in life to laboratory mice. - Clinically, rapamycin carries immunosuppressive liabilities, demonstrating the need for safer, targeted compounds that tune longevity pathways without impairing the immune system.

---

[13:00](https://www.youtube.com/watch?v=V48M5j-6zdE&t=780s) Q&A with Matt Ridley: Drugs Versus Genetic Editing

Following her presentation, moderator Matt Ridley joins Kenyon on stage to explore the bioethical and practical applications of her research. Ridley asks whether her findings imply that, ethical limits aside, researchers could engineer human embryos from scratch to produce dramatically longer-lived human beings. Kenyon clarifies that her therapeutic ambitions center strictly on pharmacology rather than germline engineering. Drug compounds bind reversibly to proteins to modulate their signaling intensity, meaning that if a patient discontinues the medication, baseline protein function promptly returns.

Kenyon warns that attempting permanent genetic ablation would be profoundly dangerous because components like insulin, IGF-1, and TOR are critical physiological regulators. When asked about permanently rewriting these core networks, Cynthia Kenyon replies: “If you knock them out completely, then you're very sick.” Achieving therapeutic longevity requires subtle, calibrated adjustments to balance cellular defense against normal growth and metabolic regulation. She highlights that scientists are exploring alternative biochemical entry points to activate FOXO downstream or through collateral signaling pathways that bypass insulin and IGF-1 entirely, minimizing side effects.

- Small-molecule drugs offer reversibility and titratable dosing, avoiding the severe health consequences of permanently disabling essential metabolic genes. - Downstream activation of FOXO offers a therapeutic alternative to upstream pathway inhibition, avoiding insulin signaling side effects.

---

[14:19](https://www.youtube.com/watch?v=V48M5j-6zdE&t=859s) Negligible Senescence, Stress Resistance, and Extending Youthspan

Ridley redirects the conversation to the concept of negligible senescence—organisms in the natural world that exhibit no measurable signs of biological aging. Kenyon affirms the phenomenon and points to Blanding's turtles as an example. When researchers examine tagged individuals verified to be 70 years old, they are physically indistinguishable from 20-year-olds; furthermore, the 70-year-old turtles actually demonstrate superior nesting site selection and yield a larger number of offspring each year. Similar lack of detectable decline occurs in specific avian species, such as terns.

While science has not fully decoded why these organisms defy typical biological breakdown, comparative biology offers notable clues. Cells collected from long-lived birds demonstrate heightened resilience against severe environmental challenges, displaying marked resistance to high temperatures and oxidative insults like hydrogen peroxide. This heightened physiological resilience matches the exact phenotype displayed by Kenyon's mutant worms and mice. The basal set points of metabolic and repair pathways in long-lived birds appear naturally calibrated to preserve tissue integrity over prolonged timelines, contrasting with the fast-running set points of short-lived roundworms.

In closing, Ridley asks whether the true objective of this work is preventing mortality or expanding the healthy portion of human life. Kenyon agrees, clarifying that the aim is to stretch the duration of youth. Drawing an analogy to human-canine interactions, Kenyon describes how a dog might observe its owner and marvel that the human does not deteriorate within the dog's compressed lifespan. In the same way, Kenyon envisions developing interventions that will allow humans to step outside their current biological limits and inhabit that extended, resilient youthspan.

- Tagged 70-year-old Blanding's turtles show no physical decay compared to young adults, exhibiting improved reproductive output and superior habitat navigation. - Cells isolated from long-lived avian species show pronounced resistance to heat shock and oxidative stressors such as hydrogen peroxide ($H_2O_2$). - The primary objective of longevity science is extending human healthspan and youthful vitality rather than simply prolonging frail old age.

## Notable quotes > [00:15](https://www.youtube.com/watch?v=V48M5j-6zdE&t=15s) If you could change one of the genes in an experiment, an aging gene, maybe you could slow down aging and extend lifespan. — Cynthia Kenyon

## Mentioned Cynthia Kenyon, Matt Ridley, Caenorhabditis elegans, daf-2, FOXO, IGF-1, TOR, Rapamycin, Blanding's turtle

## Video description http://www.ted.com What controls aging? Biochemist Cynthia Kenyon has found a simple genetic mutation that can double the lifespan of a simple worm, C. Elegans. The lessons from that discovery, and others, are pointing to how we might one day significantly extend youthful human life.

TEDTalks is a daily video podcast of the best talks and performances from the TED Conference, where the world's leading thinkers and doers give the talk of their lives in 18 minutes. Featured speakers have included Al Gore on climate change, Philippe Starck on design, Jill Bolte Taylor on observing her own stroke, Nicholas Negroponte on One Laptop per Child, Jane Goodall on chimpanzees, Bill Gates on malaria and mosquitoes, Pattie Maes on the "Sixth Sense" wearable tech, and "Lost" producer JJ Abrams on the allure of mystery. TED stands for Technology, Entertainment, Design, and TEDTalks cover these topics as well as science, business, development and the arts. Closed captions and translated subtitles in a variety of languages are now available on TED.com, at http://www.ted.com/translate.

[Source](https://www.youtube.com/watch?v=V48M5j-6zdE)

中文简报

肯扬靶向激素受体使寿命翻倍并延缓疾病抑制保守的胰岛素和IGF-1信号传导可通过FOXO激活细胞修复网络，证明衰老受基因调控，且单一药物疗法可同时预防多种与年龄相关的疾病。辛西娅·肯扬挑战了衰老仅仅是不可避免的磨损这一传统生物学观点，证明寿命从根本上受基因调控。通过突变微型秀丽隐杆线虫体内的daf-2激素受体，她的实验室在线虫保持年轻与活力的同时使其寿命翻倍，该效应由FOXO转录因子介导，激活了广泛的细胞修复与防御程序。肯扬指出，这一古老的胰岛素/IGF-1信号通路在果蝇、小鼠和人类中均具有保守性，且天然受体和FOXO变异在人类百岁老人中频繁出现。她的工作并未寻求生殖系基因编辑，而是侧重于开发可逆的小分子药物（例如TOR等营养感应通路的抑制剂），以同时延缓多种与衰老相关的慢性疾病，并延长健康的年轻期。 daf-2激素受体的单一基因突变使秀丽隐杆线虫的寿命翻倍，使其保持活跃、具有生育能力且保持生物学年轻状态的时间达到正常线虫的两倍。 (1:09) daf-2受体对应于人类的胰岛素和IGF-1受体，揭示了一条在线虫、果蝇和哺乳动物中进化保守的通路，下调该激素信号可促进长寿。 (3:41) 对人类百岁老人的研究表明，IGF-1受体基因突变和特定FOXO变异的出现率增加，证实了该通路与人类预期寿命的相关性。 (5:52) 长寿疗法旨在通过药物抑制TOR等营养感应通路或激活FOXO修复机制，在不进行永久性基因改变的情况下广泛抵御与年龄相关的慢性疾病。 (11:16)

Reading summary

Biologist Cynthia Kenyon demonstrates that aging is not an unavoidable physical decay, but a genetically regulated biological process driven by ancient hormone pathways that can be therapeutically tuned to extend youthful vitality and resist chronic disease. Genetic Regulation of Aging via daf-2 (1:09) Challenging the historic view that aging is merely the passive wearing out of biological tissues like an old shoe, Kenyon argues that lifespan diversity across species proves aging is governed by DNA. Testing this in Caenorhabditis elegans—a microscopic roundworm with an ordinary lifespan of roughly one month—her laboratory discovered that mutating a single gene out of 20,000, named daf-2, doubled the animal's lifespan to approximately two months without impairing fertility or vitality. While wild-type worms experience severe physical deterioration and immobility by two weeks of age, two-week-old daf-2 mutants remain vigorous, accumulating tissue damage at half the normal rate. Kenyon notes that the daf-2 gene encodes a transmembrane hormone receptor homologous to human receptors for insulin and insulin-like growth factor 1 (IGF-1). Because disabling the receptor doubles lifespan in worms—and lengthens life in fruit flies and mice—its standard unmutated function actively accelerates the rate of biological aging. The FOXO Defense Program and Latent Resilience (7:13) Under normal, nutrient-rich conditions, active daf-2 signaling cascades sequester a key transcription factor called FOXO outside the cell nucleus, prioritizing immediate growth and reproduction. When daf-2 signaling is reduced through mutation or dietary stress, FOXO translocates into the nucleus and binds to genomic DNA. This unlocks a latent biological survival program by transcribing a protective suite of genes, including antioxidant enzymes, DNA repair mechanisms, immune defenses, and molecular chaperones—or "caregiver genes"—that fold or recycle misfolded proteins. Kenyon illustrates this mechanism by likening FOXO to an apartment building superintendent who ordinarily leaves routine maintenance alone but coordinates extensive repair crews (roofers, window specialists, and painters) when a storm threatens. Human genetic studies reveal that specific variants of the FOXO gene are disproportionately represented in centenarians across diverse global populations, indicating that natural alterations in this defense coordinator directly influence human longevity. Therapeutic Disease Protection and Pharmacological Modulators (5:52) Kenyon emphasizes that slowing biological aging does not merely extend old-age infirmity; instead, daf-2 and insulin/IGF-1 mutants show broad resistance to major age-related afflictions, including cancer, Alzheimer's disease, and cardiovascular illness. Human clinical studies align with this mechanism, finding that centenarians in an Ashkenazi Jewish cohort in New York City are significantly more likely to carry mutations that reduce the activity of their IGF-1 receptors. Translating these pathways into medicine requires reversible pharmacology rather than permanent genetic engineering. In discussion with Matt Ridley, Kenyon warns that permanently ablating core metabolic genes like insulin, IGF-1, or the nutrient-sensing kinase TOR causes severe illness. Instead, researchers seek small molecules that titrate signaling or selectively trigger FOXO. While the TOR-inhibiting drug rapamycin extends lifespan when administered to older mice, its immunosuppressive side effects highlight the ongoing search for safer compounds. Natural Negligible Senescence and Extending Youthspan (14:19) Nature provides precedent for extended biological resilience in organisms that exhibit negligible senescence. For instance, tagged 70-year-old Blanding's turtles remain physically indistinguishable from 20-year-old adults while producing more offspring and demonstrating superior nesting behavior. Similarly, cells from long-lived bird species like terns demonstrate heightened cellular resistance when exposed to severe heat shock and oxidative chemicals like hydrogen peroxide. Kenyon clarifies that the primary objective of longevity research is not simply postponing death, but stretching the duration of health and youthful resilience. By targeting ancient nutrient-sensing networks, biomedical researchers aim to calibrate human cells toward the heightened cellular maintenance and stress resistance naturally present in long-lived species. While manipulating longevity pathways like insulin/IGF-1 and TOR presents a unified model for resisting multiple age-related illnesses at once, translating these findings to human medicine depends on developing targeted, reversible drugs that activate cellular defenses without causing metabolic disease or immunosuppressive toxicity.

精炼阅读摘要

分子生物学家 Cynthia Kenyon 指出，衰老并非不可逆转的物理磨损，而是由演化上高度保守的激素与基因信号通路主动调控的生物学过程；通过药物微调这些机制，有望在延缓衰老的同时预防多种老年慢性疾病。打破磨损论：从线虫突变到单基因延寿 (0:15) 传统生物学界曾长期将衰老视作生命组织不可避免的被动损耗，宛如一双逐渐磨破的旧鞋。然而，不同物种间寿命的巨大差异表明，衰老速率本质上由基因组决定。为验证能否通过遗传干预改变寿命，Kenyon 实验室选用成虫自然寿命仅约一个月的秀丽隐杆线虫（Caenorhabditis elegans）进行随机基因突变筛选。结果发现，仅改变线虫约两万个基因中的一个——daf-2，就能使其寿命延长一倍至两个月左右。在视频记录中，两周龄的普通野生型线虫已陷入严重的衰老瘫痪，仅头部能轻微抽动；而相同日龄的 daf-2 突变线虫依然活动矫健、保持完全生殖力，老化速度仅为普通线虫的一半。这一实验证明，衰老进程并非不可动摇的物理常数，单个基因的改变即可在保留青春活力的同时将生存期翻倍。保守的胰岛素样通路与人类长寿密码 (3:41) 分子解析显示，daf-2 基因编码的是一种跨膜激素受体，其结构与人类的胰岛素受体及胰岛素样生长因子1（IGF-1）受体同源。当该受体功能受损时线虫反而寿命翻倍，这意味着在未突变的野生型生物体内，该激素受体的常规功能实际上是在加速衰老。后续研究在果蝇和小鼠中改变对应通路亦取得了显著延寿效果，证明这套在丰饶时期偏向生长、繁殖而加速损耗的调控系统，在演化上具有极高的保守性。这一机制与人类健康高度相关。针对纽约阿什肯纳兹犹太百岁老人的基因研究发现，活至90或100岁的老人携带 IGF-1 受体活性降低突变的比例显著高于普通人群。此外，相关信号受阻的动物模型表现出对癌症、阿尔茨海默病及心血管疾病的极强抗性，表明减缓生物学老化速率有望成为一并预防多种老年慢性病的综合策略。细胞应急总管：FOXO 转录因子的全面修复机制 (7:13) 受体信号如何统领整机衰老？Kenyon 团队阐明了其下游的分子级联机制：在正常充足养分环境下，激活的 daf-2 受体会触发连锁反应，将关键基因调控蛋白 FOXO 阻隔在细胞核外；而当受体受损或外界处于压力断食状态时，FOXO 获得释放进入细胞核，并结合基因组全面启动细胞防御工程。这些被激活的下游基因包括中和氧化应激的抗氧化剂、协助蛋白质正确折叠或回收的分子伴侣（被比喻为“照料者”基因）、DNA 修复酶以及免疫防御分子。 Kenyon 将 FOXO 的运作比作公寓管理员。在风平浪静时管理员疏于修缮，而一旦接到暴风雨即将来临的警报，管理员便会迅速致电调动屋顶修缮工、窗户工、油漆工与地板工进驻维护。即便暴风雨未至，这种被全面强化的建筑也能经受更长时间的磨损。全球多项长寿人群调查证实，百岁老人携带特定 FOXO 基因变异的频率明显偏高，显示动物体内原本就存在未被充分利用的长寿潜能。药物转化路径：以雷帕霉素与 TOR 抑制为例 (11:16) 为将实验室发现转化为临床可用的抗衰疗法，Kenyon 团队已转向人源细胞系筛选能够在不改变基因组的前提下激活 FOXO 的小分子化合物。相比于胰岛素和 IGF-1 信号通路，另一个受到密切关注的靶点是营养感应激酶 TOR（雷帕霉素靶蛋白）。抑制线虫、果蝇与小鼠的 TOR 基因同样能延长寿命，且临床上已存在直接结合并抑制该激酶的现有药物——雷帕霉素。在小鼠实验中，即使在相当于人类60岁的老年阶段给药，雷帕霉素依然能有效延长其寿命。尽管 Kenyon 明确警告公众不可自行尝试服用该药——因其在临床上作为免疫抑制剂用于抗器官移植排斥，具有免疫抑制等副作用——但这证明了通过药理学靶向养分感知途径延寿的可行性，未来的研发重点在于开发更特异、低毒性的靶向分子。药理调节与可忽略衰老：目标在于延长健康青春期 (13:00) 在与 Matt Ridley 的对话中，Kenyon 明确将自身研发路线界定为可逆的药理学微调，而非胚胎基因编辑。她解释道，胰岛素、IGF-1 与 TOR 是机体代谢必需的核心调控枢纽，若永久完全敲除会导致严重疾病；小分子药物具备剂量可调与停药可逆的特性，也可以通过下游旁路温和激活 FOXO，从而避开严重的代谢副反应。针对自然界中如布兰丁龟及燕鸥等在数十年间无可见功能退化甚至生殖力上升的“可忽略衰老”生物，细胞学实验显示这些长寿鸟类细胞对高温及过氧化氢等氧化损伤具有天然的强抵抗力，其基底代谢与修复设定点天生处于更持久的稳态。Kenyon 强调，长寿科学的核心目的绝非延长体弱多病的残年，而是拓展生命的健康期与青春跨度，使机体长期维持强韧与活力。线虫与人类群体的数据证实了衰老速率受基因网络调控，但现有先导化合物如雷帕霉素伴随明显的免疫抑制毒性，如何在避开关键代谢通路受损的前提下安全、精准地调控人体 FOXO 及下游网络，仍是该转化医学路径的核心未决问题。

Source quotes

[0:15] Cynthia Kenyon: If you could change one of the genes in an experiment, an aging gene, maybe you could slow down aging and extend lifespan.

Original transcript

[0:15] Have you ever wanted to stay young a little longer [0:18] and put off aging? [0:20] This is a dream of the ages. [0:23] But scientists have for a long time [0:25] thought this just was never going to be possible. [0:27] They thought you just wear out, there's nothing you can do about it -- [0:30] kind of like an old shoe. [0:32] But if you look in nature, [0:34] you see that different kinds of animals [0:36] can have really different lifespans. [0:38] Now these animals are different from one another, [0:40] because they have different genes. [0:42] So that suggests [0:44] that somewhere in these genes, somewhere in the DNA, [0:46] are genes for aging, [0:48] genes that allow them to have different lifespans. [0:50] So if there are genes like that, [0:52] then you can imagine that, [0:54] if you could change one of the genes in an experiment, [0:56] an aging gene, [0:58] maybe you could slow down aging and extend lifespan. [1:01] And if you could do that, then you could find the genes for aging. [1:04] And if they exist and you can find them, [1:06] then maybe one could eventually do something about it. [1:09] So we've set out to look for genes that control aging. [1:12] And we didn't study any of these animals. [1:15] Instead, we studied a little, tiny, round worm called C. elegans, [1:18] which is just about the size of a comma in a sentence. [1:21] And we were really optimistic that we could find something [1:24] because there had been a report of a long-lived mutant. [1:27] So we started to change genes at random, [1:29] looking for long-lived animals. [1:31] And we were very lucky to find [1:33] that mutations that damage one single gene called daf-2 [1:37] doubled the lifespan of the little worm. [1:40] So you can see in black, after a month -- [1:42] they're very short-lived; that's why we like to study them [1:44] for studies of aging -- [1:46] in black, after a month, the normal worms are all dead. [1:49] But at that time, [1:51] most of the mutant worms are still alive. [1:53] And it isn't until twice as long [1:55] that they're all dead. [1:57] And now I want to show what they actually look like in this movie here. [2:00] So the first thing you're going to see [2:02] is the normal worm [2:04] when it's about college student age -- a young adult. [2:07] It's quite a cute little fellow. [2:10] And next you're going to see the long-lived mutant when it's young. [2:13] So this animal is going to live twice as long. [2:15] Is it miserable? It doesn't seem to be. [2:17] It's active. You can't tell the difference really. [2:20] And they can be completely fertile -- [2:22] have the same number of progeny as the normal worms do. [2:24] Now get out your handkerchiefs here. [2:26] You're going to see, in just two weeks, [2:28] the normal worms are old. [2:30] You can see the little head moving down at the bottom there. [2:33] But everything else is just lying there. [2:35] The animal's clearly in the nursing home. [2:37] And if you look at the tissues of the animal, they're starting to deteriorate. [2:40] You know, even if you've never seen one of these little C. elegans -- [2:42] which probably most of you haven't seen one -- [2:44] you can tell they're old -- isn't that interesting? [2:47] So there's something about aging that's kind of universal. [2:50] And now here is the daf-2 mutant. [2:53] One gene is changed out of 20,000, and look at it. [2:55] It's the same age, but it's not in the nursing home; [2:58] it's going skiing. [3:01] This is what's really cool: it's aging more slowly. [3:04] It takes this worm two days [3:06] to age as much as the normal worm ages in one day. [3:08] And when I tell people about this, [3:10] they tend to think of maybe an 80 or 90 year-old person [3:14] who looks really good for being 90 or 80. [3:16] But it's really more like this: [3:18] let's say you're a 30 year-old guy -- or in your 30s -- [3:21] and you're a bachelor and you're dating people. [3:23] And you meet someone you really like, you get to know her. [3:26] And you're in a restaurant, and you say, "Well how old are you?" [3:29] She says, "I'm 60." [3:31] That's what it's like. And you would never know. [3:33] You would never know, until she told you. [3:35] (Laughter) [3:39] Okay. [3:41] So what is the daf-2 gene? [3:43] Well as you know, genes, which are part of the DNA, [3:45] they're instructions to make a protein that does something. [3:48] And the daf-2 gene [3:50] encodes a hormone receptor. [3:52] So what you see in the picture there [3:54] is a cell with a hormone receptor in red [3:56] punching through the edge of the cell. [3:58] So part of it is like a baseball glove. [4:00] Part of it's on the outside, [4:02] and it's catching the hormone as it comes by in green. [4:04] And the other part is on the inside [4:06] where it sends signals into the cell. [4:08] Okay, so what is the daf-2 receptor [4:10] telling the inside of the cell? [4:12] I just told you that, if you make a mutation in the daf-2 gene cell, [4:15] that you get a receptor that doesn't work as well; [4:17] the animal lives longer. [4:19] So that means that the normal function of this hormone receptor [4:22] is to speed up aging. [4:24] That's what that arrow means. [4:26] It speeds up aging. It makes it go faster. [4:28] So it's like the animal has the grim reaper inside of itself, [4:30] speeding up aging. [4:32] So this is altogether really, really interesting. [4:35] It says that aging is subject to control by the genes, [4:38] and specifically by hormones. [4:41] So what kind of hormones are these? [4:43] There's lots of hormones. There's testosterone, adrenalin. [4:45] You know about a lot of them. [4:47] These hormones are similar [4:49] to hormones that we have in our bodies. [4:51] The daf-2 hormone receptor [4:53] is very similar to the receptor [4:55] for the hormone insulin and IGF-1. [4:58] Now you've all heard of at least insulin. [5:00] Insulin is a hormone that promotes the uptake of nutrients [5:03] into your tissues after you eat a meal. [5:05] And the hormone IGF-1 promotes growth. [5:08] So these functions were known for these hormones for a long time, [5:11] but our studies suggested [5:13] that maybe they had a third function that nobody knew about -- [5:15] maybe they also affect aging. [5:17] And it's looking like that's the case. [5:19] So after we made our discoveries with little C. elegans, [5:22] people who worked on other kinds of animals [5:24] started asking, if we made the same daf-2 mutation, [5:27] the hormone receptor mutation, in other animals, [5:30] will they live longer? [5:32] And that is the case in flies. [5:34] If you change this hormone pathway in flies, they live longer. [5:37] And also in mice -- and mice are mammals like us. [5:40] So it's an ancient pathway, [5:42] because it must have arisen a long time ago in evolution [5:44] such that it still works in all these animals. [5:47] And also, the common precursor also gave rise to people. [5:50] So maybe it's working in people the same way. [5:52] And there are hints of this. [5:54] So for example, there was one study that was done [5:56] in a population of Ashkenazi Jews in New York City. [5:59] And just like any population, [6:01] most of the people live to be about 70 or 80, [6:04] but some live to be 90 or 100. [6:06] And what they found [6:08] was that people who lived to 90 or 100 [6:11] were more likely to have daf-2 mutations -- [6:14] that is, changes in the gene [6:16] that encodes the receptor for IGF-1. [6:18] And these changes made the gene not act as well [6:23] as the normal gene would have acted. [6:25] It damaged the gene. [6:27] So those are hints [6:29] suggesting that humans are susceptible [6:31] to the effects of the hormones for aging. [6:33] So the next question, of course, is: [6:35] Is there any effect on age-related disease? [6:38] As you age, you're much more likely [6:40] to get cancer, Alzheimer's disease, [6:42] heart disease, all sorts of diseases. [6:44] It turns out that these long-lived mutants [6:46] are more resistant to all these diseases. [6:48] They hardly get cancer, [6:50] and when they do it's not as severe. [6:52] So it's really interesting, and it makes sense in a way, [6:54] that they're still young, [6:56] so why would they be getting diseases of aging until their old? [7:00] So it suggests [7:02] that, if we could have a therapeutic or a pill to take [7:05] to replicate some of these effects in humans, [7:07] maybe we would have a way [7:09] of combating lots of different age-related diseases [7:11] all at once. [7:13] So how can a hormone ultimately affect the rate of aging? [7:15] How could that work? [7:17] Well it turns out that in the daf-2 mutants, [7:20] a whole lot of genes are switched on in the DNA [7:23] that encode proteins that protect the cells and the tissues, [7:26] and repair damage. [7:28] And the way that they're switched on [7:31] is by a gene regulator protein called FOXO. [7:34] So in a daf-2 mutant -- [7:36] you see that I have the X drawn here through the receptor. [7:38] The receptor isn't working as well. [7:40] Under those conditions, the FOXO protein in blue [7:43] has gone into the nucleus -- [7:45] that little compartment there in the middle of the cell -- [7:47] and it's sitting down on a gene binding to it. [7:49] You see one gene. There are lots of genes actually that bind on FOXO. [7:51] And it's just sitting on one of them. [7:53] So FOXO turns on a lot of genes. [7:55] And the genes it turns on includes antioxidant genes, [7:58] genes I call carrot-giver genes, [8:00] whose protein products [8:02] actually help other proteins to function well -- [8:04] to fold correctly and function correctly. [8:06] And it can also escort them to the garbage cans of the cell [8:09] and recycle them if they're damaged. [8:11] DNA repair genes [8:13] are more active in these animals. [8:15] And the immune system is more active. [8:17] And many of these different genes, we've shown, [8:20] actually contribute to the long lifespan of the daf-2 mutant. [8:23] So it's really interesting. [8:25] These animals have within them [8:27] the latent capacity to live much longer than they normally do. [8:30] They have the ability [8:32] to protect themselves from many kinds of damage, [8:34] which we think makes them live longer. [8:37] So what about the normal worm? [8:39] Well when the daf-2 receptor is active, [8:42] then it triggers a series of events [8:44] that prevent FOXO [8:46] from getting into the nucleus where the DNA is. [8:49] So it can't turn the genes on. [8:51] That's how it works. That's why we don't see the long lifespan, [8:53] until we have the daf-2 mutant. [8:55] But what good is this for the worm? [8:57] Well we think that insulin and IGF-1 hormones [9:00] are hormones that are particularly active [9:02] under favorable conditions -- in the good times -- [9:04] when food is plentiful and there's not a lot of stress in the environment. [9:07] Then they promote the uptake of nutrients. [9:09] You can store the food, use it for energy, [9:12] grow, etc. [9:14] But what we think is that, under conditions of stress, [9:17] the levels of these hormones drop -- [9:19] for example, having limited food supply. [9:22] And that, we think, [9:24] is registered by the animal as a danger signal, [9:26] a signal that things are not okay [9:28] and that it should roll out its protective capacity. [9:31] So it activates FOXO, FOXO goes to the DNA, [9:34] and that triggers the expression of these genes [9:36] that improves the ability of the cell [9:38] to protect itself and repair itself. [9:40] And that's why we think the animals live longer. [9:42] So you can think of FOXO [9:44] as being like a building superintendent. [9:47] So maybe he's a little bit lazy, [9:49] but he's there, he's taking care of the building. [9:51] But it's deteriorating. [9:53] And then suddenly, he learns that there's going to be a hurricane. [9:56] So he doesn't actually do anything himself. [9:58] He gets on the telephone -- [10:00] just like FOXO gets on the DNA -- [10:02] and he calls up [10:04] the roofer, the window person, [10:06] the painter, the floor person. [10:09] And they all come and they fortify the house. [10:11] And then the hurricane comes through, [10:13] and the house is in much better condition than it would normally have been in. [10:15] And not only that, it can also just last longer, [10:18] even if there isn't a hurricane. [10:20] So that's the concept here [10:22] for how we think this life extension ability exists. [10:26] Now the really cool thing about FOXO [10:28] is that there are different forms of it. [10:30] We all have FOXO genes, [10:33] but we don't all have exactly the same form of the FOXO gene. [10:36] Just like we all have eyes, [10:38] but some of us have blue eyes and some of us have brown eyes. [10:41] And there are certain forms of the FOXO gene [10:44] that have found to be more frequently present [10:46] in people who live to be 90 or 100. [10:48] And that's the case all over the world, [10:50] as you can see from these stars. [10:52] And each one of these stars represents a population [10:54] where scientists have asked, [10:56] "Okay, are there differences in the type of FOXO genes [10:58] among people who live a really long time?" and there are. [11:01] We don't know the details of how this works, [11:03] but we do know then [11:05] that FOXO genes can impact [11:07] the lifespan of people. [11:09] And that means that, maybe if we tweak it a little bit, [11:12] we can increase the health and longevity of people. [11:16] So this is really exciting to me. [11:18] A FOXO is a protein that we found in these little, round worms [11:20] to affect lifespan, [11:22] and here it affects lifespan in people. [11:24] So we've been trying in our lab now [11:26] to develop drugs [11:28] that will activate this FOXO cell [11:30] using human cells now [11:32] in order to try and come up with drugs [11:34] that will delay aging and age-related diseases. [11:37] And I'm really optimistic that this is going to work. [11:40] There are lots of different proteins that are known to affect aging. [11:43] And for at least one of them, there is a drug. [11:46] There's one called TOR, which is another nutrient sensor, [11:48] like the insulin pathway. [11:50] And mutations that damage the TOR gene -- [11:52] just like the daf-2 mutations -- [11:54] extend lifespan in worms [11:56] and flies and mice. [11:59] But in this case, there's already a drug called rapamycin [12:01] that binds to the TOR protein [12:03] and inhibits its activity. [12:05] And you can take rapamycin and give it to a mouse -- [12:08] even when it's pretty old, like age 60 for a human, [12:10] that old for a mouse -- [12:12] if you give the mouse rapamycin, [12:14] it will live longer. [12:16] Now I don't want you all to go out taking rapamycin. [12:18] It is a drug for people, [12:20] but the reason is it suppresses the immune system. [12:23] So people take it to prevent organ transplants from being rejected. [12:27] So this may not be the perfect drug [12:29] for staying young longer. [12:31] But still, here in the year 2011, [12:34] there's a drug that you can give to mice at a pretty old age [12:36] that will extend their lifespan, [12:38] which comes out of this science [12:40] that's been done in all these different animals. [12:42] So I'm really optimistic, [12:44] and I think it won't be too long, I hope, [12:46] before this age-old dream begins to come true. [12:49] Thank you. [12:51] (Applause) [13:00] Matt Ridley: Thank you, Cynthia. [13:03] Let me get this straight. [13:05] Although you're looking for a drug [13:07] that can solve aging [13:09] in old men like me, [13:12] what you could do now pretty well in the lab, [13:15] if you were allowed ethically, [13:17] is start a human life from scratch [13:20] with altered genes that would make it live for a lot longer? [13:23] CK: Ah, so the kinds of drugs I was talking about [13:26] would not change the genes, [13:28] they would just bind to the protein itself [13:31] and change its activity. [13:33] So if you stop taking the drug, the protein would go back to normal. [13:36] You could change the genes in principle. [13:39] There isn't the technology to do that. [13:41] But I don't think that's a good idea. [13:43] And the reason is [13:45] that these hormones, [13:47] like the insulin and the IGF hormones and the TOR pathway, [13:50] they're essential. [13:52] If you knock them out completely, then you're very sick. [13:55] So it might be that you would just have to fine tune it very carefully [13:58] to get the benefits without getting any problems. [14:01] And I think that's much better, [14:03] that kind of control would be much better as a drug. [14:05] And also, there are other ways of activating FOXO [14:08] that don't even involve insulin or IGF-1 [14:10] that might even be safer. [14:12] MR: I wasn't suggesting that I was going to go and do it, but ... [14:15] (Laughter) [14:19] There's a phenomenon which you have written about and spoken about, [14:23] which is a negligible senescence. [14:26] There are some creatures on this planet already [14:28] that don't really do aging. [14:31] Just move to one side for us, if you would. [14:34] CK: There are. There are some animals that don't seem to age. [14:37] For example, there are some tortoises called Blanding's turtles. [14:41] And they grow to be about this size. [14:43] And they've been tagged, and they've been found to be 70 years old. [14:46] And when you look at these 70 year-old turtles, [14:48] you can't tell the difference, just by looking, [14:51] between those turtles and 20 year-old turtles. [14:53] And the 70 year-old ones, [14:55] actually they're better at scouting out the good nesting places, [14:58] and they also have more progeny every year. [15:01] And there are other examples of these kinds of animals, [15:04] like turns, certain kinds of birds are like this. [15:07] And nobody knows if they really can live forever, [15:09] or what keeps them from aging. [15:11] It's not clear. [15:13] If you look at birds, which live a long time, [15:16] cells from the birds tend to be more resistant [15:19] to a lot of different environmental stresses [15:21] like high temperature [15:23] or hydrogen peroxide, things like that. [15:25] And our long-lived mutants are too. [15:27] They're more resistant to these kinds of stresses. [15:29] So it could be that the pathways that I've been talking about, [15:32] which are set to run really quickly in the worm, [15:35] have a different normal set point [15:38] in something like a bird, so that a bird can live a lot longer. [15:41] And maybe they're even set really differently [15:43] in animals with no senescence at all -- but we don't know. [15:46] MR: But what you're talking about here [15:48] is not extending human lifespan [15:51] by preventing death, [15:53] so much as extending human youthspan. [15:55] CK: Yes, that's right. [15:57] It's more like, say, if you were a dog. [15:59] You notice that you're getting old, and you look at your human [16:01] and you think, "Why isn't this human getting old?" [16:03] They're not getting old in the dog's lifespan. [16:05] It's more like that. [16:07] But now we're the human looking out and imagining a different human. [16:11] MR: Thank you very much indeed, Cynthia Kenyon. [16:14] (Applause)