Committee

Popular weight-loss drugs may do more than help people shed pounds. They might also melt away the years. Drug giants Eli Lilly and Novo Nordisk say patients taking their drugs age less quickly, according to readouts from molecular “aging clocks.” Such clocks assess a person’s biological age by looking at changes to DNA that accumulate with time, or, in newer versions, by tracking levels of key proteins. Both companies found that overweight or diabetic patients taking the drugs, called GLP-1s, had reduced biological age compared to those taking a placebo, although the difference varied widely, depending on which type of clock was used, and what organ was tested.  Overall, the difference was around “two to three years,” according to Nikolaj Roed, a global project leader at Novo, who says the company has been seeing “improved biological age in our patients across trials and across different tissues.”  The findings add to wide speculation among scientists that GLP-1 drugs, as they are known, are acting on basic causes of aging and might be a true longevity treatment. “Two years is a pretty strong effect, in my book,” says Steve Horvath, a professor at the University of California, Los Angeles, who’s credited with inventing aging clocks. Horvath says the emerging data could provide “evidence that these GLP-1 drugs are actually what is known as geroprotectors, medications that slow or possibly even reverse biologic aging.” The companies shared their findings over the weekend during Aging Research & Drug Discovery, a conference devoted to seeking scientific remedies for old age. While that quest has not yet produced any clear-cut success, some scientists now think Novo’s drug semaglutide (sold under the names Ozempic and Wegovy) is coming close. “In an unhealthy population, I do think it’s an anti-aging drug,” says Vadim Gladyshev, a Harvard biologist who assisted Novo with its molecular measurements. “But in a healthy population, no one knows.” The drugs cause weight loss by stimulating a receptor, GLP-1, that tells your brain you’re not hungry. Yet real-world studies have shown much wider benefit. The drugs improve kidney function, reduce blood pressure, and even sharply cut the overall chance of death. “If the question is,‘Can semaglutide reach several diseases relevant to health span and aging?’ we know we can say the answer is yes,” said Alejandro Aguayo-Orozco, a senior scientific director at Novo, the Danish drug giant, during the meeting. The next question to answer, he said, is whether such effects are accompanied by changes to molecular measures of biological aging: “When you intervene with semaglutide, does it actually move the clocks in any direction? And the answer is yes.”  The company found that, over time, the drugs cause a wide slowdown in aging clocks—as much as 4 years in the case of a clock that looks at heart proteins. “I think it’s pretty clear that the organ age is shifting,” said Aguayo-Orozco. The studies are also a huge boost for the science of aging clocks. Although these measures reflect a person’s age, it’s been uncertain if they are useful as true biomarkers. Now clock makers have evidence  that their readouts show a drop in age when people take drugs with broad, well-demonstrated benefits.   “The clock people have been pushing for a decade to get this kind of study done,” says Yuge Ji, a biologist who previously worked in the field and now runs a startup, Reflector Bio. “It’s huge for them.” As part of its study, Novo took blood draws from 10,052 people, half on the drug and half on a placebo. Their blood, collected at the start of the study as well as months later, was then measured with “proteomic clocks,” which use levels of key proteins to predict a person’s age and risk of dying.  Scientists at Eli Lilly performed similar research on their GLP-1 drug, tirzepatide, using so-called “epigenetic” clocks that assess age by counting accumulated changes to DNA. Lilly’s study was smaller, but also found that for the most part, molecular time moved more slowly for people on the drug.   “All the clocks are telling a consistent story that we’re seeing a reduction in age,” Kevin Duffin, vice president for aging research at Lilly, said during the conference. “It’s not like we’re going to reverse age by 30 years or something, but it’s a significant reduction.” The molecules have become the best selling drugs in the world,, with Lilly’s tirzepatide, sold as Mounjaro for diabetes and Zepbound for obesity, topping the list with more than $36 billion in revenue to the company last year. Novo’s semaglutide, also sold under more than one name, was a close second. Alex Zhavoronkov, the founder of Insilico Medicine, and the organizer of the Boston meeting, says that extending lives by even one year across the world’s population would be equal to tens of millions of lifetimes.   Last month Zhavoronkov showed that one of his company’s drugs, for a lung disease, also reversed the signals from aging clocks. That drug is experimental, but Zhavoronkov has sought to promote the idea that humanity is entering a new era of longevity medicines. He also disclosed during the event that he has been “microdosing” the available weight-loss drugs, even though he is not overweight. “I am on tirzepatide and I am an equal-opportunity injector of semaglutide as well,” Zhavoronkov said. It was part of an effort to directly raise the question of whether the first mass-market anti-aging remedy is already here. “Do you think a reasonable person should start taking semaglutide?” he asked Aguayo-Orozco, the Novo scientist, in front of a crowded audience. “I am not a physician. I cannot answer that question,” Aguayo-Orozco replied. Several people cautioned that GLP-1 drugs do have side effects, including muscle loss. That is one reason they might not help most people, says Horvath, who says he isn’t ready to take the drugs himself, although he’s thought about it. “Clearly, the drugs have many benefits in obese people, but I did not yet see sufficient evidence that they will benefit skinny

Over the summer I talked to the CEO of Springboards, a startup building an LLM that’s designed to come up with a wider variety of responses than its mainstream rivals do. At the start of the call, he said something that’s been stuck in my head since: “We often say that we’re a self-loathing AI company. We don’t know if we really like what we’re doing.” “I guess that makes me a self-loathing AI journalist,” I replied. It was a joke! I love my job. But I do not love many of the things the technology I write about has become: warped by hype, steered by zealots, inescapable. The CEO of Springboards and I are far from alone. Around the world, a love/hate attitude toward AI is very much the vibe right now. On the one hand, public feelings are souring fast. According to the Pew Research Center, more adults in the US think AI will have a negative impact on them personally, and on society in general, than expect a positive one. The pessimism is strongest among the young. More than half of people worldwide say that AI products and services make them nervous, according to a report from Stanford University. In a Gallup poll in May, 71% of US adults said they would oppose construction of a new AI data center in their area, far more than the 53% who said they would oppose a new nuclear power plant. And in an NBC poll in March, AI was less popular than ICE. Yet the number of people using AI is still skyrocketing. ChatGPT hit a billion monthly users in May, according to the market analysis firm Sensor Tower. Google DeepMind’s Gemini is close behind, logging 950 million users in July. According to Pew, half of US adults now say they use a chatbot, more than twice the number who said they did in 2023. One in four people say they do so every day. And it’s a global habit: More than a third of adults across all 38 OECD countries (a group of the world’s wealthiest democracies) report having used generative AI tools in the last three months. All these surveys paint a picture of two contradictory truths: A lot of people really do not like AI and a lot of people cannot get enough of it. What’s going on? It’s possible that these are two distinct groups, but I doubt it. The numbers don’t add up unless the Venn diagram is on its way to being a circle. It’s also possible that the more people use AI, the more negative their opinions about it will be. There’s at least a correlation to back this up: The Global North, where adoption is highest, skews pessimistic. In the Global South, where adoption levels are lower, people are more optimistic. But here’s what I really think is going on: When people say they hate AI it’s not the technology they dislike but, rather, the relentless drive of the companies behind it to push the tech upon us in as many ways as possible. They’re telling us to brace for the biggest social and economic upheaval in generations. How do they expect people to feel? In many ways, we’ve been here before. We saw a similar dynamic play out with social media over the last 20 years. Billions flocked to Facebook and Twitter despite mounting techlash against the companies that ran those services. Ditto for Google search. With social media there wasn’t much anyone could do. Quitting a platform meant losing all your content and connections, giving you the choice to suck it up or start over. But with AI there’s still a chance for people to have some sway. There’s certainly more political appetite for regulation this time around. All 50 US states have either passed or proposed laws governing the development and deployment of AI, creating a patchwork of more than 2,100 bills across the country—a tenfold increase in three years.  And with a number of top-class open-source alternatives to Google and OpenAI and Anthropic already on the market, there’s also (for now, at least) the potential for more consumer choice and the market pressure that goes with it.  I don’t want to be naïve. Trillion-dollar companies are hard to move. But what comes next is not as inevitable as those companies often imply. When I asked the Springboards CEO why his firm was developing a new model if he didn’t really like AI, he told me there was no walking back from LLMs—but you could still make them do something different.  Here’s hoping we see a lot more of something different: Clarity about what AI can and cannot do and, crucially, a technology that’s not sold as if it’s about to take over the world.

On an afternoon in Seoul in March 2016, I watched a program I helped build put a stone on the fifth line of a Go board in what looked like a gift to its human opponent. Move 37 in game two of the five-game match looked so absurd that some commentators thought it was a programming glitch. It wasn’t. AlphaGo won the game, ultimately triumphing 4-1 over Lee Sedol, one of the greatest professional Go players of all time. “I thought AlphaGo was based on probability calculation and that it was merely a machine,” Lee said afterwards. “But when I saw this move, I changed my mind. Surely, AlphaGo is creative.”  When Deep Blue defeated then reigning world chess champion Garry Kasparov in 1997, it did so by looking six to eight moves ahead per player and evaluating 200 million chess positions per second, using rules hard-coded by humans. Go is a vastly more complex game. A stone’s worth depends on how distant groups and territory unfold over dozens of moves. Computing even a fraction of the possible outcomes would take a supercomputer billions of years. To win, AlphaGo had to sense who was ahead at a glance and even invent moves no human had thought to play. That is why many accounts of AlphaGo’s match against Lee portray move 37 as a flash of pure machine intuition. But that is a misunderstanding. It was actually AlphaGo’s powers of reasoning that made this creative choice—and these are powers that today’s AI lacks. If we want future AI systems to produce trustworthy results and really novel insights in fields like science and medicine, we need to equip them with genuine reasoning capabilities of this kind. AlphaGo is made up of two systems. The first, its policy network, was trained to guess what move a strong human would play. This “intuitive” part regarded move 37 as nothing special—a play that had a roughly one in 10,000 chance of being made by an expert human player. What made AlphaGo choose it was the program’s search machinery, which looked beyond immediate plausibility and weighed the future consequences of proposed moves. It explicitly constructed and searched a game tree with thousands of branches, each representing a different possible future.  A well-known theory in the behavioral sciences, popularized by Daniel Kahneman, distinguishes between two modes of human thought: System 1 is fast, gut-level, effortless; system 2, slow, step-by-step, and deliberative. AlphaGo offered a striking machine analogue of that split. Its networks supplied the hunches—this move looks promising, this position looks won—and its search supplied the deliberation, testing those hunches against the moves and countermoves that would follow. As in human cognition, neither half works alone. Intuition alone would never have opted for move 37, and brute-force search would have struggled to sieve through all the many possible moves. This is strikingly different from the way today’s AI models work. A large language model picks the next token, over and over. That amounts to system 1 in action—fast, associative, and surprisingly good pattern completion across almost every subject people write about. Not long after ChatGPT debuted, the field realized that language fluency alone falls short of true usefulness. The apparent solution was to make models that deliberate: Instead of answering immediately, they can now generate intermediate steps that decompose a problem, carry forward partial results, and influence subsequent reasoning—a process known as chain of thought. The gains have proved real, above all in mathematics and coding. But unlike AlphaGo’s search, this does not introduce a genuinely separate reasoning mechanism: The intermediate reasoning is still produced by the same next-token prediction process, iterated for longer before the model commits to an answer. Three shortcomings prevent what chatbots do from qualifying as reasoning (in a way that a scientist might recognize). First, these models typically maintain no explicit, persistent, and inspectable epistemic state. There is no open ledger that lays out the hypotheses a model is considering, the confidence it has in various explanations, the evidence it’s weighing, and the unresolved questions it’s holding onto—all things that should be systematically revised as new information arrives. Second, they lack a clean separation between what the system knows and how it manipulates that knowledge. Knowledge and reasoning are inextricably interwoven in the weights of the neural network—there is no independent, explicitly represented set of beliefs. Third, while the chains of thought chatbots produce look like deliberation, research has demonstrated that the bots often concoct them after the fact, reaching an answer by one route but reporting another. This is a problem because in the high-stakes applications we all care about, such as medicine, engineering, and scientific research, it matters not only what a system concludes but also how it arrives at its conclusion. When mistakes happen—for example, in medical diagnosis and treatment—we need to be able to pinpoint what went wrong: Was the system’s reasoning at fault, did it draw on invalid evidence, or did it make incorrect assumptions?  This is why I recently left my position at Google DeepMind. I believe we need a fresh approach to machine reasoning—one that draws on AlphaGo’s architecture. AlphaGo maintains a record of what it knows about a given position: the game tree. This data structure contains all the variations, the possible futures, that AlphaGo has considered, each move and position being annotated with judgments made by its neural networks. As its reasoning progresses, AlphaGo updates the game tree and eventually synthesizes the information in it to decide which move to make.  Similarly, for general reasoning a system should maintain an epistemic state that represents what the system holds as settled, what it doubts, what it has ruled out, which questions stay open. Reasoning can then be understood as a sequence of moves that change the epistemic state to advance knowledge and reduce uncertainty: deducing consequences, breaking problems into parts, and—crucially—deciding what question to ask, calculation to perform, or experiment to run next. Of course, open-world reasoning is harder than playing a board

This week, I officially signed up for an unusual competition. One that rewards competitors for getting younger. I recently turned 40, and I don’t need reminding that both time and my chronological age only tick forward. But this game is focused on competitors’ biological ages—figures that are meant to provide a better way to measure the age-related health of our organs and bodies. Over a six-month period, around 500 of us will try to reverse our biological age as measured in a bunch of different ways. There’s even a leaderboard! The winners will include the person who shows the greatest difference between their chronological and biological age, as well as the person who manages to reverse their biological age the most. The competition is the brainchild of the neuroscientist and physician Christin Glorioso, who is also founder and CEO of NeuroAge Therapeutics. The company offers tools to track brain health and aging and is running a trial to find out if biological brain age can predict the onset of Alzheimer’s disease. Glorioso says she has several goals for the Younger contest. The first, she tells me, is to “explain to the world what aging clocks are.” Regular Checkup readers will be familiar with these tools, but for the uninitiated, they are basically designed to measure biological age. Many measure chemical signatures that form a layer on top of our DNA and seem to change with age. But others might involve looking at proteins or lipids in blood. Some are designed to measure functional health, while others predict when a person will die. There are more than a hundred clocks out there, and they probably each capture a specific aspect of the biological process of aging. These clocks are proving very useful for scientists, who use them to study aging and development in humans and many other species. But using them to estimate the biological age of an individual person is more controversial. They’re just not good enough for that yet. Part of the problem is that we don’t really understand what each clock is capturing. Glorioso hopes that data collected through the Younger contest might help answer that question. She’s hoping to generate “the world’s most comprehensive clock dataset.” Some longevity clinics try to get around the limits of biological age testing by using multiple clocks. That’s this competition’s approach too. As a standard competitor, I’ll be sending a blood spot sample to TruDiagnostic, a company that measures epigenetic chemical groups on DNA and offers to reveal an overall biological age as well as a person’s pace of aging and the biological ages of each of 11 organ systems, including the heart and brain. I’ll get a brain age score from NeuroAge once I complete the cognitive tasks on offer. I’ll also submit some physical measures like grip strength. And I’ll upload a series of selfies to an app developed by a team at Harvard that promises to tell me my face age. That’s exactly what it sounds like—an estimate of how old my face looks. I’m intrigued to see my scores, even though I know I shouldn’t put too much stock in them. The first time I took a test, four years ago, the company I used gave me a biological age that matched my chronological age, which was a little disappointing and, if I’m honest, a bit underwhelming. A year later, the same company told me I had a young heart but a relatively old brain, liver, and hormonal system. My lifestyle hasn’t changed much since then. Will the years have made much difference? (Ultra competitors—who pay $4,499 rather than the $999 cost of regular entry—are also offered a range of other blood tests and clocks, as well as MRI and DEXA scans. I’ve got complimentary press access to the standard package.) Glorioso is also hoping to gather information about the effects of some purported longevity approaches. During the competition, some participants will be offered red-light masks, access to a sauna, or other low-risk offerings that partner companies who are sponsoring the event to varying degrees might want to collect data on. “A lot of these companies just can’t afford to run [clinical] trials,” says Glorioso. She also sees the event as a public health initiative. A couple of years ago, David Sinclair, who studies aging at Harvard Medical School, and his colleagues estimated that if we could slow down aging in the general population and increase life expectancy by one year, it would save the US economy $38 trillion. The event officially kicks off in January, but around 120 people have already signed up, says Glorioso. Ultimately, she expects 500 participants. Each person’s six-month run starts as soon as they take their baseline measurements, whenever that may be. A handful of people have already started. “I think the majority of people are going to want to sign up after the holidays,” says Glorioso. “They’re not going to want to be trying to win an aging contest over Christmas and Hanukkah.” Glorioso took her own baseline measurements back in August. Those initial tests suggested that her biological age was around 10 years below her chronological age. That sounded pretty impressive to me until I looked at the leaderboard and saw that competitor @Fred had a biological age 28.8 years below his chronological age. The leaderboard is pretty sparse at the moment, as only seven people have logged their baseline measurements so far. Six of them have biological ages tracking low, but one 47-year-old has been given a biological age of 68.1. She’s competing publicly, so I can see the breakdown of her scores. The worst is for the speed at which she can stand from sitting in a chair—by that measure, she’s been given a biological age of 100. Hillary Lin, a longevity-focused physician in New York, has just started logging her baseline measurements for the competition. She tells me she’s taken biological age tests in the past and that they’ve tended to give scores below her chronological