David Shaywitz

The arrival of generative AI prompted many to worry about the adverse impact on human agency; after all, if the technology can effectively do what we’re doing, where does that leave us? 

This concern was the central focus of Reid Hoffman’s “Superagency,” which I reviewed for the WSJ earlier this year – see here.  Essentially, Hoffman argues that new technologies can take some time to adjust to, but ultimately they empower us to do more things and greater things. 

In the moment, however, that’s not how many experience the technology; in the review, I discuss a 2024 research paper out of MIT exploring the impact of generative AI on material scientists.  The technology seemed to make the researchers more productive – and apparently even more creative – but also robbed them of the aspect of their work that provided them the most satisfaction.  

As I wrote,

Mr. Hoffman, presumably, would argue that future scientists, accustomed to partnering with AI, will experience an enhanced sense of agency based on all they will be able to accomplish. Whether this forecast ultimately accords with our lived experience is the unanswered question upon which Mr. Hoffman’s cheery thesis depends.

Reid Hoffman

Recently, I’ve been thinking a lot about agency in the context of another remarkably powerful emerging technology – GLP-1 receptor agonists, the wildly popular anti-obesity medicines developed by Lilly and Novo.

According to the most recent CDC data, over 40% of Americans are categorized as suffering from obesity (defined, however imperfectly, as a BMI of 30 or higher); 9.2% of Americans suffered from extreme obesity (BMI 40 or higher).  As the CDC points outs, “This means that more than 100 million adults have obesity, and more than 22 million adults have severe obesity.”

These numbers are climbing; twenty years earlier, about 30% of Americans were classified as suffering from obesity, and 4.7% suffered from extreme obesity, according to the CDC.

Prior to the arrival of GLP-1 medicines, durably losing weight in the extraordinarily obesogenic environment that we inhabit was virtually impossible without bariatric surgery.  But not for lack of effort; millions of Americans endured cycle after cycle of desperately trying to lose weight, only to fail entirely, or to briefly succeed and then regain the weight rapidly. I can relate (see here, here).

One consequence of this pattern was a sense of futility around lifestyle changes for health.  Yes, doctors preached the benefits of “diet and exercise,” and everyone is familiar with this advice.  However, the sad reality is that the constant failure of the diet component often resulted in a broader sense of demoralization.  What’s the point of sweating on the treadmill for half an hour if you’re just going to undo the apparent benefit by scarfing down some oreos later that day?  (To be sure: there are many important intrinsic benefits of exercise, but it could be a difficult argument to make when someone is watching themselves get heavier day after day.)

The demoralization associated with failed (or being failed by) diet/nutrition programs (presumably coupled with the increased difficulty of exercising when you are heavier) thus had a cascading effect, depriving many of the absolutely extraordinary health benefits associated with physical activity, as I’ve discussed here and just this week here.

Enter the GLP-1s.  In addition to all the remarkably positive effects they seem to have on their own (including some that appear independent of weight loss, as endocrinologist Daniel Drucker notes in a recent review, here), I suspect that among the greatest health opportunities associated with GLP-1 medicines will be their enhancement of our sense of agency.

According to University of Pennsylvannia professor Martin Seligman (see my discussion here) agency boils down to the belief that “I can make a positive difference in the world.”  As I wrote,

Referencing what he describes as an extensive literature, Seligman argues that “people who have high agency are physically healthier,” adding “If you look at people with high agency holding constant the traditional risk factors, they live on average 6-8 years longer,” compared to people with low agency.

He continues, “Optimistic people—people who believe that they can control things far into the future, bounce back. They resist depression. They succeed. They try harder and give up less at school.” They do better in college than their SATs predict, he says, and do better at work. In contrast, “pessimistic people are less productive than their talents predict.” 

From a health perspective, he says “about 20 well-done studies” have shown that after accounting for “the usual risk factors,” it turns out that “being in the bottom quartile of pessimism is roughly equivalent to smoking 2-3 packs of cigarettes a day for longevity. “

The point is that according to Seligman, enhanced agency is associated with better health.  The massive opportunity I suspect GLP-1s may represent is that by allowing people – finally – to achieve mastery of their diet and appetite, these medicines might profoundly enhance our sense of agency.

Martin Seligman, Zellerbach Family Professor of Psychology, University of Pennsylvania; Founding Director, Positive Psychology Center

In addition to this being intrinsically beneficially to our health as Seligman suggests, it’s easy to imagine that success in the nutrition management will motivate many to embrace other health enhancing behaviors, including in particular exercise, which presumably will generate still more positive feedback and enhance our sense of agency even further.

In short, GLP-1s will generate what I’d call an agentic dividend that can be — and should be — leveraged to drive other healthy behaviors.

A bit optimistic? Only if GLP-1s prove financially inaccessible to most people – unfortunately, a very real possibility. 

A skeptic might also argue that GLP-1s are fundamentally a cheat – in helping us lose weight without the suffering, we don’t really acquire the mastery, and perhaps the sense of enhanced agency, that weight loss without medical assistance might provide. 

This is an understandable argument (if also somewhat dated with its emphasis on raw willpower). It’s also arguably moot since so few people were durably successful this way. I suspect that without the psychological burden of serial diet/nutrition failures, we will be far more enthusiastic about embracing additional healthy activities.

I am particularly excited by the profound opportunity here to recognize and leverage the agency enhancement that GLP-1s will provide and use it to fuel additional health-positive behaviors, starting with exercise, and building out from that foundation.

David Shaywitz

Dying, with few exceptions, has never been especially popular, and our shared interest in not dying hardly constitutes breaking news.  Nevertheless, the aspiration of living longer — and remaining healthier while doing it — appears to be all the rage.

Consider these recent headlines:

• “Why is longevity sudden so hot?” – Chrissy Farr, Second Opinion.
• “The longevity business is booming – and its scientist are clashing” – Amy Dockser Marcus, The Wall Street Journal.
• “Rise of the superhuman” – cover story, The Economist.
• “The business of promoting longevity and healthspan” – Dr. Eric Topol, Ground Truths.

There have also been a slew of longevity-focused books over the last several years; Outlive, by Dr. Peter Attia, is perhaps the best known, and has spent over ninety weeks on the New York Times Bestsellers list.  Also relevant: Dr. Howard Luks’s Longevity…Simplified: Living A Longer, Healthier Life Shouldn’t Be Complicated.

What’s going on – what accounts for this apparent surge of interest?

To oversimplify, there are two general (and not entirely distinct) lines of work that seem to account for this. 

First, there’s the biological study of longevity itself – what accounts for the intrinsic limits of lifespan, and how might this be extended?  Much of this biology, as Dockser Marcus describes in the WSJ, originated from studies in the Guarente Lab at MIT, and has been pursued by researchers including David Sinclair (now Professor in the Department of Genetics at Harvard Medical School) and Brian Kennedy (former CEO of Buck Institute for Aging, currently Distinguished Professor in Biochemistry and Physiology at the National University of Singapore).

Leonard Gaurente, Novartis professor of biology, MIT

Similar to many frontier areas, the underlying science of aging has proved particularly challenging.  As Dr. Eric Verdin, CEO and president of the Buck Institute for Research on Aging in Novato, California told Dockser Marcus,

“…the more you study something, the more you understand the complexity. There is no magic pill—even though we all would love the idea that there’s going to be something magical that solves all of your problems and prevents you from aging.”

The second area of work involves the factors that cause us to get sick and frail when we age.  Attia describes four “chronic diseases of aging,” which he calls “the Four Horsemen”:

• Cardiovascular disease
• Cancer
• Neurodegenerative disease
• Type 2 diabetes and associated metabolic conditions

Dr. Attia’s framework, shared by others, is that each of these diseases develops very slowly over time, yet we tend to intervene only relatively late in the process.  

The “goal should be to act as early as possible,” Dr. Attia argues.  “We should be proactive instead of reactive in our approach.  Changing that mindset must be the first step in attacking slow death.”

There also appears to be a shared belief that a key factor contributing to all four Horsemen (to various degrees) is metabolic dysfunction – essentially the idea that through excessive and unhealthy eating, and insufficient exercise, we develop insulin resistance, and our bodies enter a generalized pro-inflammatory state. 

This contributes not only to cardiovascular disease and type 2 diabetes, but (at least to some extent) to cancer and neurodegeneration as well.  Through focusing early on improved diet and more exercise, and monitoring progress closely, the hope is that we might delay, perhaps for many years, the arrival of the Horsemen.

Acting Without RCTs

One common attribute of many (but not all) researchers and entrepreneurs focused on either the biology of longevity or the prevention of chronic disease (or both) is a sense that action is required and warranted before definitive proof (in the form of randomized controlled trials, the gold standard of medical science) has been documented.

For example, Dockser Marcus writes,

Dismissing promising results because they aren’t definitive isn’t fair, Guarente said: “It is moving in the direction where there will be stronger and stronger data, maybe not in everything, but in some significant human health areas in the future.” 

Similarly, Attia argues (in a section titled “From evidence based to evidence informed”) that while the “purists of evidence-based medicine demand data from RCTs before doing anything (emphasis in original),” the study of longevity isn’t particularly amenable to tradition RCTs because “it would take too long to do the study” and “the interventions are very complex, particularly if they involve exercise, nutrition, and sleep.”

Thus, he says, rather than wait for definitive proof that might never come, he argues we should extrapolate aggressively and thoughtfully from what we know, and recognize we’ll not achieve “absolute certainty,” but rather it’s about managing risk.

He argues we should think about approaching our health like an investment strategy, “seeking the tactics, based on what we know now, to deliver a better-than-average return on our capital, while operating within our own tolerance of risk.”

With this context, we can appreciate the rationale underlying both the consumer longevity companies (generally focused on extensive testing) profiled in depth by Dr. Topol and the supplements promoted by some of the longevity biologists interviewed by Dockser Marcus.  Many longevity biologists are also working on developing what they hope will be FDA-approved medicines to combat aging.

We can also start to appreciate some of the critical dynamics associated with the surge in interest in longevity.  If you believe traditional medicine is either excessively conservative about assessing risk or insufficiently proactive, or both, and if you are sufficiently well-off to afford the additional testing, then longevity companies are here to serve you. 

On the other hand, Dr. Topol observes, “As is the case with the companies attempting to reverse aging, the ones marketing longevity, healthspan and advanced prevention to consumers have not yet provided any evidence for benefit.”

He continues,

That is not to say the concept behind these companies— a much broader collection of data— is wrong. My contention is that it is flawed because it is indiscriminate as to who undergoes testing and what tests (such as total body MRI or multi-cancer early detection) and when they are performed. 

As Dr. Topol points out, according to Bayes Theorem, “if the pre-test probability is low, the accuracy of the test is substantially reduced.” 

In short, the testing approach utilized by many longevity companies seems likely to generate a plethora of false positives, as well as additional testing, procedures, and anxiety. That’s a key concern for both physicians and payers — that we’ll run all these tests and waste a lot of time and money searching for problems that aren’t really there, and potentially generating new, iatrogenic problems in the process.

(Dr. Zak Kohane and colleagues described the challenge of “incidentalomas” in 2006, here; I’ve recently reviewed a book about Bayes Theorem for the WSJ here; the topic is also covered in another book I recently reviewed for the WSJ – Sir David Spiegelhalter’s The Art of Uncertainty – here.)

While today’s consumer-focused longevity companies focus on testing, the research around longevity science, while complex, as Dr. Verdin noted, remains exciting and promising.  The work could ultimately lead to FDA-approved medicines capable of resetting our intrinsic rate of aging and significantly increasing our potential lifespan.

Alignment Around Lifestyle

Despite differences in thresholds for various diagnostic tests, there seems to be remarkable alignment around lifestyle interventions that can promote longevity.  As Dr. Luks nicely summarizes (recommendations with which Attia and others seem to largely agree), key elements include:

Dr. Howard Luks, author, “Longevity… Simplified”

• Get and stay lean (now far more achievable thanks to GLP-1 medicines); eat real food.
• Move often, and ensure you engage in aerobic, muscle strengthening, and balance-promoting activities.
• Get sleep.
• Socialize.
• Have a sense of purpose.

As longtime TR readers recognize, I’m especially impressed by the impact of exercise, and I’m hardly the only one.  As Attia writes, “The data demonstrating the effectiveness of exercise on lifespan are as close to irrefutable as one can find in all human biology.”

The disproportional impact of getting the sedentary to move even a little (as I’ve discussed here) is striking:

I am especially attracted to the idea of a healthspan platform that’s rooted less in arcane laboratory testing, and more in promoting a combination of activity and agency (which I suspect GLP-1RA medicines can help propel), particularly among the motivated tech-savvy highly agentic 50+ generation I’ve referred to as “The Vanguard.”

Bottom Line

Longevity is having a moment, driven both by decades of research into the biology of aging and by research suggesting metabolic dysfunction leading to chronic inflammation may contribute to major diseases of aging, exerting a deleterious effect over a very long time.  The hope is that earlier intervention (perhaps prompted by a suggestive value on a laboratory test or imaging study) could mitigate the damage.  One concern is that if testing is performed without consideration of pre-test probabilities, many false positives will be identified and pursued.  On the other hand, GLP-1 medicines provide a profound opportunity, particularly when combined with suitable physical activity, for individuals to significantly enhance their years of healthy life.  In addition, with continued research, longevity science may one day deliver FDA-approved medicines capable of significantly increasing intrinsic human lifespan.

David Shaywitz

As economic historian Carlota Perez has described, there is typically a significant time lag between when the promise of novel technology begins to emerge and the productive deployment of this technology at scale; TR readers will recall the discussion here from June 2023.

Today, we are seeing this with generative AI, an emerging technology that everyone is still trying to get their arms around (see this TR discussion).  The inevitable uncertainty associated with these early days has hardly discouraged large consulting firms, who have all developed “AI playbooks” and are busy persuading potential corporate clients that they are lagging their peers in AI and risk impending extinction. 

A Cautionary Tale From Big Pharma

Nevertheless, meaningful (vs performative) adoption of generative AI with most large enterprises has been predictably sluggish (see this TR discussion from August 2024).

Ziv Bar-Joseph

Ziv Bar-Joseph, the former VP-Head of R&D Data and Computational Sciences at Sanofi, candidly and generously shared on LinkedIn lessons learned from his recent experience at the large French pharma. These takeaways include (emphasis added):

– Pharma moves slowly. It takes over 10 years to develop a drug. So its not surprising that planning and decision making at big pharma can look very long and frustrate potential partners (and our own employees). Some of it is just bureaucracy. But much of it is intentional. These are often decisions that will have long lasting impact and its important to get them right.

– Adoption remains a major challenge. Not because of any principled objection to AI or new technology. But rather because it is very hard to change the way people work. Other issues affecting adoption of new technology are changing needs, people leaving and change in priorities and focus.

–  Sanofi is not an AI company. While it continues to develop cutting edge AI tools, Sanofi would prefer to purchase or partner rather than build AI products internally.  This makes economic and business sense. But it can be frustrating for our internal teams, especially when the decision comes after internal work already started on a similar product (usually because at the time we started the external solution was not available).

These findings are neither unique to Sanofi nor likely to shock regular TR readers. Yet Bar-Joseph’s insights emphasize a real challenge faced by the field: how to most effectively leverage AI when it’s brutally difficult to meaningfully implement AI in large corporations at a non-glacial time scale.

Don’t Make The Tool – Implement It

One answer that seems to be emerging – at least among impassioned AI investors – is to identify focused and more manageable opportunities (vs transforming a giant pharma corporation) and drive the AI mediated change yourself.

Cass Mao, a Silicon Valley tech entrepreneur, wrote recently on LinkedIn:

I know 10 different people leaving venture investing right now to do a PE [private equity] play with AI.
The basic thesis being: more opportunity than ever right now to drive value in SMB [small and medium sized businesses] using technology. But adoption is slow, super fragmented market, a ton of competition with 100s of new tools launching every week.
“Easier” to buy a small company, drive adoption, and reap rewards via direct ownership of the bottom line – a few million in personal upside within a few years.
vs. be deploying capital in the fast moving froth, high vals, high churn, high competition. so many tools funded and fighting the distribution war, competing with similar tools to seek adoption.
you’re seeing tools that cost $20/month eliminate **tens of thousands of dollars of cost**.
better to be the SMB with 50 different ways to save $30,000, than one of 50 SaaS cos charging $240/year.

In short, she’s suggesting that:

     (a) Cheap AI tools can save a significant amount of money if deployed effectively and in the right context;

     (b) If you can identify the right opportunity (basically a job amenable to your tool, and a small organization where you can actually implement the technology), you can do better implementing the AI yourself and pocketing the revenue from the efficiency gains vs trying to sell a particular AI tool in a very crowded market.

The question, of course, is how (or whether) this can be applied to biopharma.

Consider the following approach, suitably anonymized, but inspired by a real techbio example (there are probably a number of startups trying something similar).

Let’s say you’ve identified a specific, valuable aspect of drug development where you believe your technology (AI or something else) gives you an economically valuable competitive advantage. You might believe, for example, you have a more efficient way of running clinical trials. Such a company might then seek to in-license clinical-stage assets from pharmas, execute efficient clinical development past a value inflection point, and then out-license the further de-risked assets back to pharma at a higher valuation. 

The basic strategy itself isn’t particularly original, and startups, with conviction around one asset or another, in-license molecules all the time. The difference in this case is that because you believe your technology allows you to prosecute assets more efficiently, you focus on leveraging this perceived advantage, ideally by raising sufficient money (from entranced tech VCs, say) to fund enough shots on goal. 

Through your superior efficiencies of clinical development, you hope, you have a high chance of clinical, and hence financial success. (You, and especially your tech investors, may also hope your technology allows you to identify more promising assets than skilled drug developers alone, though I’m still very skeptical about this part.)

Beware of Pyrrhic Technological Victories

The success of this type of approach will depend, of course, both on how well the technology works and how much of competitive advantage it actually delivers – does it really move the needle for the tech-enabled company? 

Consider this example from genetics: metabolism of the blood thinner warfarin is strongly influenced by two genes, CYP2C9 and VKORC1. Genetic testing can determine whether you are likely to be a “fast” or “slow” metabolizer. Yet, utilizing genetic testing turns out to offer at best minimal advantages to the traditional clinical approach of “going low and going slow,” to arrive empirically at a therapeutic dose. Thus, while it might seem in theory that genotyping technology could improve care, in practice, most doctors haven’t embraced it because the impact seems less than the aggravation.

Similarly, techbio companies need to be sure both that their technology really works and that it imparts a meaningful advantage. It’s a tough ask, but one that’s clearly attracted the interest of both investors and entrepreneurs who are convinced about the promise of AI in biopharma and are intensively pursuing the highest-leverage place in which to deploy it.