.png)
6 hours ago
1
Today, aging is cool. In 2024 alone, investors deployed about $8.5B into longevity-focused biotech companies. Aging biotech companies have entered clinical trials. The field has come a long way.
But as “aging” (and “longevity”) have become more mainstream, there’s a temptation to stretch the definition to things that don’t belong in the category. Aging is not a single process. It’s a complex interplay of multiple biological processes that, over time, become dysregulated. Understanding it as such is crucial for developing effective interventions. So it’s worth thinking about what makes something genuinely an “aging” biotech approach, and how to tell if you’re really tackling aging.
A successful aging treatment would be something that:
prevents diseases of aging, ideally more than one;
preserves a healthy function that normally declines with age (like fertility, immune function, cognitive function, resilience, or physical fitness); or
reverses the course of at least one age-related disease.
This seems pretty obvious, but it has non-trivial implications.
If the goal is to prevent or delay age-related disease and loss of function, then we’re envisioning a treatment that people start taking when they’re healthy (no clinical disease). It would look like “Take this pill and reduce your risk of heart attacks, diabetes, cancer, and so on.”
That’s not unprecedented. People with high cholesterol take statins to reduce heart attack risk, and people taking GLP-1 receptor agonists for diabetes or obesity have a lower risk of all-cause mortality.
But it does present special challenges.
A drug that prevents age-related diseases needs to be safe enough for a healthy person to take. And, it needs to target a clinical endpoint that’s relevant to preventing age-related disease, but doesn’t take an unrealistically long time to test in trials.
Alternatively, if your goal is to reverse age-related disease, you’re often trying to intervene on seriously damaged tissue.
Tackling a neurodegenerative disorder? Once a patient is diagnosed with Alzheimer’s, for example, they’ve already lost millions of neurons. Permanently.
Likewise, some other diseases of aging, like chronic kidney disease and cirrhosis, involve fibrosis, in which healthy tissue is converted to scar tissue.
In other words, reversing the progression of degenerative, age-related disorders would require replacing healthy cells that have been lost, or transforming damaged tissue into healthy tissue – essentially, true regenerative medicine or cellular reprogramming.
Some disease indications are generally bad signs for an R&D program’s prospects for ever coming up with a bona fide aging therapeutic.
This is not to say that developing treatments for these diseases isn’t worthwhile. It’s just a different endeavor from aging.
Cancer is so deadly that we’ll tolerate pretty severe side effects in a cancer drug that works at all. Most cancer drugs work by killing cancer cells (and, we hope, not too many healthy cells). So, few effective cancer treatments are safe enough for a healthy person to take. Oncology is generally the wrong disease indication if you’re looking for a geroprotector.
Some genetic disorders cause a so-called “accelerated aging” syndrome, or “progeria,” that in some ways mimics the health problems of old age. However, these are usually single-gene disorders, and real aging is more complex; monogenic aging differs from polygenic aging. A progeria treatment might be life-changing for these rare-disease patients, but it’s unlikely to translate to the average elderly person.
Some molecular biomarkers (such as molecules found in the blood) change in levels with age. Some of these age-related changes, such as alterations in DNA methylation, have even been interpreted as “aging clocks,” with the idea that they can indicate an individual’s “biological age” or “rate of aging.” A natural idea is to try to target aging biomarkers – if you change the level of the biomarker, perhaps you’ll have “rejuvenated” the organism!
There are a few wrong equivocations:
One that has become a central debate in the aging field is that “aging biomarkers” are derived from studies indicating correlation, not causation. If you make an “old” biomarker phenotype look “youthful,” have you reversed a process of decline and dysfunction? Or have you blocked a protective mechanism that’s more needed in old age? Without more information, we can’t tell.
Then, even correlational studies generally show an association between the aging clock and chronological age, not actually an individual’s risk of death or disease in the future! Correlations between aging clocks and mortality tend to be weak, and shrink in bigger samples and after correcting for cell type distributions. Many “aging biomarkers” and “aging clocks” are worse at predicting future mortality than simply asking patients to rate themselves on overall “health.” Manipulating clocks could actually be neutral or even harmful.
If a startup claims to target aging biomarkers or aging clocks, or to measure them as a diagnostic, without committing to generating additional evidence that they’re doing something causally meaningful, they’re probably not going to move the needle on aging.
Some disease indications and endpoints seem especially promising because they’re relevant to the majority of elderly people and a wide range of age-related diseases, but are themselves measurable and clinically significant in the short term.
Loss of muscle mass and strength with age is an important risk factor for dangerous falls and general disease vulnerability. Simple physical-function tests such as gait speed or the Short Physical Performance Battery (SPPB) consistently outperform individual blood biomarkers, and often rival sophisticated multi-marker panels, in predicting long-term mortality. A treatment that makes older adults less frail will make a vast difference to quality of life and likely reduce the risk of multiple age-related diseases.
Age-related immune dysfunction underlies multiple diseases of aging, from cancer to dementia. The aging immune system simultaneously causes more inflammation and is less effective at fighting off pathogens and cancers. Improving immune function tackles a root cause of age-related disease, but reducing the risk of (especially respiratory) infection is also immediately measurable and consequential, since influenza and COVID-19 are leading causes of death in the elderly.
Obesity, insulin resistance, and metabolic syndrome are risk factors for nearly every age-related disease, and there’s now strong precedent for treating them with drugs directly, with or without a diabetes diagnosis. Because metabolic dysfunction precedes cardiovascular, neurodegenerative, and fibrotic disease, drugs that target it could be viable “geroprotectors.” GLP-1 agonists already show substantial cardio-renal benefits in humans and, in preclinical work, reverse multi-omic aging signatures and modestly extend lifespan in fast-aging mice. So far, though, no study has lengthened lifespan in healthy mammals or humans.
Fibrosis, like chronic inflammation, is a tissue-level process that contributes to multiple diseases of aging. Some specific diseases, like idiopathic pulmonary fibrosis, are almost purely disorders of excessive fibrosis, and a generally effective and safe anti-fibrotic drug may have a broader range of applications.
Some neurodegenerative diseases, like Parkinson’s, have a prodrome that can begin to show distinctive symptoms (like loss of sense of smell and certain sleep disorders) up to twenty years before Parkinson’s itself is diagnosed.
Treatments that target prodromes, with the aim of both treating immediate symptoms and preventing or delaying disease onset, have a better chance of striking at the root of these disorders.
Humans live a long time, so a longitudinal study that looks at all-cause mortality is expensive and slow. But such studies do exist and can show mortality benefits from chronic use of some drugs. Also, veterinary aging biotechs like Loyal are now directly treating lifespan as an endpoint, and are entering the clinic to test whether their drug candidates can help dogs live longer. Directly measuring longevity and all-cause mortality isn’t easy, but those who do it can provide unquestionable evidence that they’re really tackling aging and age-related disease.
There are also methodological approaches that seem like good signs that a company is likely to make progress on aging and age-related disease.
Aged organisms are different from “disease models” that may simply have a single experimentally or genetically induced problem. Approaches to aging therapeutics are more credible if they work on:
Aged organisms (e.g., mice >20 months)
Spontaneously occurring disease in model organisms
Human-derived tissue samples from older patients
They are also more credible if they draw from evidence about aging in non-model organisms (i.e., not the usual lab mice, rats, flies, and worms).
Delay – postpone the onset of age-related decline (the most common strategy).
Replace – swap aged or damaged tissue for youthful counterparts (cell therapies, 3D-printed organs, xenotransplants).
Restore – reverse cellular aging (partial or full reprogramming), pending safety validation.
Pause – induce biological stasis (torpor, hibernation, cryopreservation) to halt the clock, useful for organ preservation.
These approaches, as this blog has previously noted, tend to involve newer therapeutic modalities like cell and gene therapies, not just the more traditional small molecule drugs.
