Could GLP-1 drugs be anti-aging medications?

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GLP-1 medications for weight loss and diabetes appear to slow the body’s aging processes, a sign that the blockbuster drugs could ultimately help people live longer.

The idea that these medications may extend lifespan isn’t exactly far-fetched; it’s more of an extension of what they’ve already been shown to do. Studies have found that along with helping people shed fat and control blood sugar, GLP-1 drugs improve the health of many different parts of the body, lowering the risk of heart, kidney and liver disease, for example, and reducing sleep apnea and inflammation, which contribute to loss of health and function as people age.

“Aging is the biggest risk factor for many diseases, and if we can target aging itself, we might be able to treat all kinds of diseases that are associated with aging,” said Dr. Danica Chen, a professor at the University of California at Berkeley who studies calorie restriction and aging.

Now, scientists have turned their attention to biological markers of aging to better understand exactly how GLP-1 drugs may affect the aging process.

The new research conducted in mice and people is early, and scientists say they don’t know whether the benefits apply only to people who are overweight or have diabetes when they start taking them medications, or if they could also slow aging in people who are normal weight and otherwise healthy.

For that reason, experts say it’s too early for people to use this medication solely in the hopes of living longer.

“There are people who are biohacking and taking these agents who are not either diabetic or obese, and the question there is what happens in lean younger non-diabetic individuals, especially over the long term,” said Dr. James Kirkland, who directs the Center for Advanced Gerotherapeutics at Cedars-Sinai Medical Center in Los Angeles. “My concern is that people could overread some of this stuff.”

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Kirkland says the metrics used in the new studies – which are based on measurements of epigenetics, the way genes are turned on and off in the body and the measures of proteins our bodies make over time — are still in development, and although they’re useful for studies in larger groups of people, they’re not very informative for individuals, though many companies have begun marketing these types of tests to curious consumers.

“They can vary tremendously from day to day within a person,” Kirkland said.

Still, these early findings are generating excitement.

“We’re seeing a reduction in age,” somewhere around three to six years, said Dr. Kevin Duffin, vice president of aging research at Eli Lilly. Lilly makes tirzepatide, which is sold as Zepbound for weight loss and Mounjaro for diabetes management.

“It’s not the panacea. It’s not like we’re going to reduce age by 30 years or something, but it’s a significant reduction,” Duffin told a packed audience at the recent Aging Research and Drug Discovery conference in Boston.

Duffin presented new data from Lilly’s Surmount V clinical trial, which randomly assigned more than 700 adults who were overweight but did not have diabetes to use either tirzepatide or semaglutide for 72 weeks. The aging study looked at a group of 71 participants from the study who were on tirzepatide and over the age of 50.

By measuring how certain genes in their blood were turned off and on during the course of the study, the researchers were able to look at changes to so-called epigenetic clocks, which reveal the biological age of their organs and tissues, as opposed to their calendar age.

Over the course of the study, Duffin explained, they would have expected a person to age 1.38 years in chronological time. But in the small group of study participants who were using tirzepatide, biological clocks advanced more slowly. Across different types of epigenetic clocks, the researchers saw an average change of between 1.1 years and 0.7 years in biological aging. Some biological clocks actually went backward, suggesting that some organs and tissues were acting younger than when people started the study.

Duffin acknowledged that the study has limitations. There was no placebo group who were not using any weight loss meds to compare against the people on tirzepatide, for example, and the follow-up was relatively brief.

From what the researchers could see, the anti-aging effects seemed to get stronger over time, however, so they hope to follow people for longer in the next trial.

“Be very interesting to see what happens at four or five years after treatment with a GLP-1,” Duffin said.

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It’s also not yet clear whether the slowing of the biological aging is due to weight loss or if there could be some effect of the GLP-1 drugs independently. There’s a lot of good evidence, for example, that eating a calorie-restricted diet — cutting calories by about 25% — has anti-aging effects and extends the lifespan of many types of animals.

Studies have shown that weight loss surgery, which helps people drop significant amounts of weight, slows biological aging, too. But it’s very hard to achieve weight loss or cut calories that much through willpower alone, making the role of medications and surgery critical.

In one of the first questions after his talk, an audience member asked Duffin whether he had repeated the experiment in someone who was not overweight, to see if the effect was a result of weight loss or something else the drug was doing.

“We get this question all the time,” Duffin said. “The bottom line is, these drugs work through [blood sugar] reduction and through weight loss, and the effects we’re seeing are mostly due to that.”

The drug semaglutide, which is sold as Wegovy and Ozempic, shows many of the same anti-aging benefits, according to new research from drugmaker Novo Nordisk.

By measuring changes to proteins in the body over time in people using semaglutide, the company’s scientists found that it reduced the heart’s biological age by two to four years compared with a placebo, and it reduced the age of organs such as the lung, kidney, brain and pancreas by one to four years. The study was published as a preprint , ahead of peer review.

The researchers said the effects were not completely explained by weight loss, blood sugar control or inflammation.

Study author Dr. Alejandro Aguayo-Orozco, senior global director of cardiometabolic research and development at Novo Nordisk, said the benefits of GLP-1 medications had thus far been measured one disease at a time – but what if the effects were bigger than that?

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“If we’re touching so many diseases, are we actually also touching something that is systemic across these diseases? Is it aging? Is it health span?” he asked at the recent Aging Research and Drug Discovery meeting.

Recent research in mice tried to answer some of these questions more directly. Mice typically live about two years, so it’s easier to follow them throughout their lifespan than it is to do the same for humans.

Scientists at the University of California at Berkeley took 20-month-old mice – roughly the age equivalent of 60-year-old humans – and gave them injections of semaglutide or a placebo for the rest of their lives.

They were roughly the same body weight at the start of the study. But the mice on semaglutide ate less and lost weight, and they lived longer than the mice that got placebo injections. The semaglutide-treated mice had an average lifespan of 834 days, about the same as 80 human years, while the mice injected with placebos lived 742 total days, or roughly 75 human years.

From booze to betting to fitness: How GLP-1s are changing behavior

To test whether it was the weight loss or the drug specifically that was responsible for the benefit, researchers next reduced the amount of calories fed to another group of mice by 25% — about the same amount of reduction seen in mice on semaglutide.

Like the GLP-1-treated mice, the calorie-restricted mice lived longer, but there were some differences between the two groups, said Chen at UC Berkeley, who helped lead the research, which was published in the journal Nature .

For many tissue functions the group looked at, especially related to muscle function and mobility, the semaglutide-treated mice and calorie-restricted mice performed about the same.

But mice on semaglutide showed some advantages. They functioned better at thinking and at finding their way out of a maze, and they were better able to manage their blood sugar than mice on calorie restriction alone.

“So that just means that it’s more than just a calorie restriction and has additional benefits,” Chen said.

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用于减肥和治疗糖尿病的 GLP-1 药物似乎可以减缓身体的衰老过程，这表明这些重磅药物最终可能有助于人们延长寿命。

这些药物可能延长寿命的说法并非牵强附会；这更像是对其现有功效的延伸。研究发现，除了帮助人们减脂和控制血糖外，GLP-1 类药物还能改善身体多个部位的健康状况，例如降低心脏病、肾病和肝病的风险，并减轻睡眠呼吸暂停和炎症——这些都是导致老年人健康状况和机能下降的因素。

“衰老是许多疾病的最大风险因素，如果我们能够针对衰老本身，我们或许就能治疗所有与衰老相关的疾病，”加州大学伯克利分校研究卡路里限制和衰老的教授丹妮卡·陈博士说。

现在，科学家们将注意力转向衰老的生物标志物，以更好地了解 GLP-1 药物究竟如何影响衰老过程。

这项在小鼠和人体上进行的新研究尚处于早期阶段，科学家们表示，他们还不清楚这些益处是否仅适用于开始服用药物时超重或患有糖尿病的人，或者是否也能延缓体重正常且身体健康的人的衰老。

因此，专家表示，现在就让人们仅仅为了延长寿命而使用这种药物还为时过早。

“有些人通过生物黑客技术服用这些药物，但他们既不是糖尿病患者也不是肥胖者。问题在于，对于体型偏瘦、年轻且非糖尿病患者来说，长期服用这些药物会发生什么？”洛杉矶西达赛奈医疗中心高级老年治疗中心主任詹姆斯·柯克兰博士说，“我担心人们可能会过度解读这些信息。”

衰老可以像疾病一样治疗吗？科学家们正在开始探索这个问题。

柯克兰表示，新研究中使用的指标——基于表观遗传学的测量，即基因在体内开启和关闭的方式以及我们身体随时间推移产生的蛋白质的测量——仍在开发中，虽然它们对更大规模人群的研究很有用，但对个人而言信息量不大，尽管许多公司已经开始向好奇的消费者推销这类测试。

“即使是同一个人，每天的症状也可能大相径庭，”柯克兰说。

不过，这些早期发现已经引起了人们的兴奋。

“我们发现患者的年龄有所下降，”礼来公司衰老研究副总裁凯文·达芬博士说，下降幅度大约在三到六岁之间。礼来公司生产的替拉帕肽以Zepbound（用于减肥）和Mounjaro（用于糖尿病管理）的商品名销售。

“这不是万灵药。我们不可能让年龄减少 30 岁左右，但这确实是一个显著的减少，”达芬在最近于波士顿举行的衰老研究和药物发现大会上对座无虚席的听众说道。

达芬公布了礼来公司Surmount V临床试验的最新数据。该试验随机分配了700多名超重但未患糖尿病的成年人，分别接受替泽帕肽或索玛鲁肽治疗72周。这项针对老年人的研究选取了其中71名接受替泽帕肽治疗且年龄超过50岁的参与者进行分析。

通过测量受试者血液中某些基因在研究过程中如何开启和关闭，研究人员能够观察所谓的表观遗传时钟的变化，从而揭示受试者器官和组织的生物学年龄，而不是他们的日历年龄。

达芬解释说，在研究过程中，他们原本预期受试者的实际年龄会增长1.38岁。但在使用替拉帕肽的一小部分研究参与者中，生物钟的推进速度却更慢。研究人员发现，在不同类型的表观遗传时钟中，生物衰老的平均变化在0.7年到1.1年之间。一些生物钟甚至出现了倒退，这表明某些器官和组织的运作状态比受试者开始研究时更年轻。

达芬承认这项研究存在局限性。例如，没有设置未使用任何减肥药物的安慰剂组与服用替拉帕肽的患者进行比较，而且随访时间相对较短。

研究人员观察到，抗衰老效果似乎随着时间的推移而增强，因此他们希望在下一次试验中对受试者进行更长时间的跟踪观察。

“看看接受 GLP-1 治疗四五年后会发生什么，这将非常有趣，”达芬说。

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这项测试能衡量我们的衰老程度吗？

目前尚不清楚延缓生物衰老是否是由于体重减轻所致，还是GLP-1类药物本身具有独立作用。例如，已有大量证据表明，限制卡路里摄入（减少约25%的卡路里）具有抗衰老作用，并能延长多种动物的寿命。

研究表明，减肥手术不仅能帮助人们显著减轻体重，还能延缓生物衰老。但仅凭意志力很难实现如此大的减肥目标或大幅减少卡路里摄入，因此药物和手术的作用至关重要。

在演讲结束后的第一个问题中，一位听众问达芬，他是否在体重正常的人身上重复了这项实验，以看看这种效果是体重减轻的结果，还是药物的其他作用。

“我们经常被问到这个问题，”达芬说。“归根结底，这些药物的作用机制是通过降低血糖和减轻体重，我们看到的效果主要也是由于这些原因。”

根据制药公司诺和诺德的最新研究，以 Wegovy 和 Ozempic 为商品名销售的药物索马鲁肽具有许多相同的抗衰老功效。

通过测量服用索玛鲁肽的患者体内蛋白质随时间的变化，该公司科学家发现，与安慰剂相比，索玛鲁肽可使心脏的生物年龄减少2至4岁，并使肺、肾、脑和胰腺等器官的生物年龄减少1至4岁。该研究以预印本形式发表，尚未经过同行评审。

研究人员表示，这些影响并不能完全用体重减轻、血糖控制或炎症来解释。

该研究的作者、诺和诺德公司心血管代谢研究与开发高级全球总监 Alejandro Aguayo-Orozco 博士表示，迄今为止，GLP-1 药物的益处都是一次只针对一种疾病进行衡量的——但如果其效果远不止于此呢？

Roberto Pfeil//dpa/picture alliance/Getty Images

“如果我们研究了这么多疾病，我们是否也研究了这些疾病中存在的系统性问题？是衰老吗？是健康寿命吗？”他在最近的衰老研究和药物发现会议上问道。

最近对小鼠的研究试图更直接地回答其中一些问题。小鼠的寿命通常约为两年，因此与人类相比，更容易追踪它们的一生。

加州大学伯克利分校的科学家们选取了 20 个月大的小鼠（大致相当于 60 岁的人类），并在它们的余生中给它们注射司美格鲁肽或安慰剂。

研究开始时，两组小鼠的体重大致相同。但接受索玛鲁肽治疗的小鼠食量减少，体重下降，而且寿命比接受安慰剂注射的小鼠更长。接受索玛鲁肽治疗的小鼠平均寿命为834天，约相当于人类的80岁；而接受安慰剂注射的小鼠平均寿命为742天，约相当于人类的75岁。

从饮酒、赌博到健身：GLP-1 如何改变行为

为了检验是体重减轻还是药物本身带来了益处，研究人员接下来将另一组小鼠的卡路里摄入量减少了 25%——这与服用司美格鲁肽的小鼠的卡路里减少量大致相同。

与接受 GLP-1 治疗的小鼠一样，限制卡路里摄入的小鼠寿命更长，但两组小鼠之间存在一些差异。加州大学伯克利分校的陈教授参与领导了这项研究，该研究成果发表在《自然》杂志上。

研究小组观察了许多组织功能，特别是与肌肉功能和活动能力相关的功能，结果显示，接受索玛鲁肽治疗的小鼠和限制卡路里摄入的小鼠的表现大致相同。

但接受索玛鲁肽治疗的小鼠表现出一些优势。它们的思维能力更强，更容易走出迷宫，而且比单纯限制卡路里摄入的小鼠更能控制血糖。

“所以这意味着它不仅仅是限制卡路里摄入，还有其他益处，”陈说。