LongeCityNews Last Updated: 22 April 2026 - 09:16 AM

Human life expectancy has increased steadily over time since the 1800s, but much of the analysis is focused on life expectancy at birth, where the dominant effects involve improvements in early life survival. More interesting are the measures of remaining life expectancy at some adult age. These measures also increase over time, but more slowly. In recent decades, the increase in life expectancy at age 65 has increased at a pace that is on the order of one year in every ten. Since this happened over a span of time in which little to no meaningful progress was made in deliberately treating aging as a medical condition, it is reasonable to ask how it happened. As is usual in matters of human epidemiology, firm answers are hard to come by. Correlations are easy to generate, but it is challenging to prove causation, or determine the relative importance of different contributions to an observed outcome.

Nonetheless, researchers have generated insight from the statistics of human mortality. For example work from fifteen years ago shows an equal split between (a) reduced premature mortality, compressing mortality to a smaller range of later ages, and (b) a reduction in mortality in those later ages. It is an open question as to whether these are both manifestations of the same underlying mechanisms, resulting from improvements in public health, reduced exposure to severe infection, general advances in medicine, and so forth. If we accumulate less damage along the way, do we also tend to live longer? Reliability theory suggests this is the case, building on what is known of the statistics of the failure of complex arrays of redundant parts.

In one sense a reduced mortality due to intrinsic causes and age-related disease is equivalent to a slower pace of aging, as aging is defined by its effects on mortality. In another sense, whether aging has been slowed depends on how one defines aging - at the level of mechanisms, capacity, and cellular biology rather than at the level of epidemiology and mortality, that is. Today's open access paper is a consideration of whether we can or should say that increased life expectancy means that aging is slowed versus postponed, and that is a distinction that really does force one to engage with how exactly aging is defined. What, mechanistically, is aging, exactly, if the pace of aging does not change, but the age of onset of aging can vary? This is a very different view to that provided by reliability theory.

The rhythm of aging: Stability and drift in the individual rate of senescence

Human aging is marked by a steady rise in the risk of dying with age - a process demographers call senescence. Over the past century, life expectancy has risen dramatically, but is this because we are aging slower, or simply starting it later? This has been framed as a testable hypothesis: the rate at which the risk of dying increases with age for humans may be a basic biological constant that is very similar and perhaps invariant across individuals and over time. From this perspective, gains in life expectancy would reflect delayed aging, not a change in the underlying process of senescence. But if the rate of aging is truly changing, it would suggest that the biological processes underlying senescence are more responsive to environmental, behavioral, or historical conditions than previously assumed.

We focus on actuarial senescence - the age-related rise in mortality risk - which, in most adult populations, shows an exponential increase in mortality with age, well described by the Gompertz law. The Gompertz slope measures how quickly risk accelerates as deterioration accumulates. Though not a direct biological measure, is widely used as a proxy for the rate of aging. Empirical tests of this hypothesis have yielded mixed findings. This may suggest that the variations in could be historically driven. Period events - such as wars, pandemics, and economic crises - strike multiple cohorts at once, just at different ages, and their lasting consequences can subtly distort the mortality patterns within each exposed cohort through cumulative shifts. As a consequence, when we estimate cohort by cohort, we may be tracing not a pure signal of the aging process, but the lasting effects of these shared historical events. As these shocks accumulate over time, they can produce variations that mimic a change in the slope of mortality, even if the underlying biological rate is constant.

We ask whether cohort-to-cohort variation in the Gompertz slope reflects a shift in the pace of aging or the effects of period shocks. We test this idea using a framework that decomposes the pace of senescence into three components: a biological baseline, a long-term trend, and the cumulative impact of period shocks. Applying this to cohort mortality data above age 80 from 12 countries, we find that once period shocks are accounted for, there is no statistical evidence of a long-term trend, consistent with the hypothesis. Analyses using lower starting ages yield the same qualitative conclusion. Rather than indicating a change in the process that drives senescence, these variations are consistent with echoes of shared historical events. Together, these findings indicate no evidence of a persistent directional change in the individual rate of aging.

This stability does not imply that aging is fixed in all aspects. Over the past century, survival has shifted toward older ages and life expectancy has increased substantially. These improvements may primarily reflect declines in baseline and background mortality rather than persistent changes in the rate at which mortality rises with age. In demographic terms, the onset of senescence may be postponed even if its tempo remains stable.

According to a new study, rapamycin probably interferes with exercise, blunting its effects in older human subjects. This result, however, might be specific to the particular protocol.

Can they work together?

Physical activity is one of the most potent pro-longevity interventions currently available [2]. Rapamycin is the undisputed champion of small molecules for extending lifespan in animal models, although human data is scarce. It would seem sensible to combine those two for a synergistic effect, but they are in an intrinsic tug-of-war with each other.

Rapamycin blocks mTORC1, an important regulator of nutrient sensing, switching the organism from the “building mode” to the “maintenance mode.” Growth (anabolism) is attenuated, while intracellular cleanup (autophagy) is upregulated, which results in robust longevity gains in model organisms. Exercise, on the other hand, builds muscle mass and endurance by increasing anabolic activity. This conflict has unclear outcomes for humans in real life.

The “cycling hypothesis” suggests that spacing out rapamycin administration might help mitigate the tension with exercise, giving us the best of the two worlds. To test it, an international group of researchers, supported by Lifespan Research Institute as a fiscal sponsor, conducted a trial, the results of which have been published in the Journal of Cachexia, Sarcopenia and Muscle.

“Lifespan Research Institute has been a wonderful partner that enabled this trial to be done. I’m incredibly thankful for their support,” said Brad Stanfield, one of the authors, to Lifespan News. “Going in, we hoped the ‘cycling hypothesis’ would alleviate anabolic resistance (meaning that older adults would see improved muscle performance when rapamycin was combined with exercise, compared to just exercise alone).”

Rapamycin seems to make things worse

The team recruited 40 sedentary adults aged 65-85 who were treated once a week with 6 mg of rapamycin (sirolimus) or placebo, alongside a 13-week home exercise program, with dosing timed to the rest day furthest from the next workout. The question of the randomized, double-blind, and placebo-controlled trial was simple: does weekly rapamycin help, hurt, or have no effect on the functional gains people get from exercise?

“We hoped that weekly rapamycin dosed 24 hours after the last workout would preserve the autophagy benefits of mTORC1 inhibition while leaving room for post-exercise adaptation. It didn’t,” said Stanfield. “One explanation is that rapamycin’s about 62-hour half-life likely kept mTORC1 partially inhibited into the next training week.”

Both groups did the same home exercise program three times a week: a resistance component of 30-second chair-stands, progressed by asking participants to do more reps in the fixed 30-second window, and an endurance component on a magnetic-resistance stationary bike that ramped from 10 minutes at Level 1 to 25 minutes at Level 5 over the 13 weeks. The authors did not measure pharmacodynamic markers to confirm that mTORC1 was actually being inhibited as expected, instead relying on prior literature showing that 5-6 mg weekly does so for 5-7 days.

Both groups improved their chair-stand performance over 13 weeks. The placebo group improved more, although this primary endpoint did not reach statistical significance. Two prespecified sensitivity analyses sharpened the picture with statistically significant results favoring the placebo group: the complete-case analysis (only participants with both baseline and Week-13 data) and the per-protocol analysis (participants who completed 75% or more of doses and exercise sessions). The other functional measurements, including six-minute walk distance and grip strength, all pointed in the same direction (a win for placebo) but fell short of reaching statistical significance.

Consistency matters here: across several independent outcomes, the rapamycin arm underperformed, which is exactly what you’d expect if the drug is genuinely blunting adaptation to exercise. The study was powered to detect only large effects, so smaller-but-real effects would be expected to miss significance.

The team also measured exploratory mechanistic outcomes, including epigenetic clocks and C-reactive protein (CRP), a blood marker of systemic inflammation. Surprisingly, rapamycin participants had higher inflammation on average, although this was driven by two outliers with unusually high CRP levels; excluding them reduced the difference to less than 1 mg/L. So, at the very least, rapamycin did not meaningfully reduce inflammation, contrary to a common hypothesized benefit of the drug.

Four epigenetic age measurements, PCGrimAge, SystemsAge, OMICmAge, and DunedinPACE, showed mixed, non-significant trends. PCGrimAge trended toward a younger biological age in the rapamycin arm, but the other three clocks showed no pattern or slightly favored placebo. Several lab parameters also shifted modestly in the rapamycin arm: HbA1c and LDL cholesterol both rose slightly.

17 of 20 participants in each arm reported at least one adverse event, but the total number of events was higher in the rapamycin arm. Events judged to be possibly or probably drug-related were more than twice as common in the rapamycin arm (35% vs. 15%). Only one serious adverse event occurred, and it was in the rapamycin arm: a participant developed community-acquired pneumonia, requiring hospitalization. Because rapamycin is immunosuppressive, a causal contribution cannot be excluded.

It’s still too early to tell

“This is a single dose, schedule, and population study, so it isn’t a verdict on rapamycin generally,” said Stanfield. “But within that window, the signal is internally consistent: the primary outcome pointed against enhancement, every secondary functional outcome directionally favored placebo, and the per-protocol effect size was large. That pattern is hard to dismiss as noise, and it lines up with classic rodent overload studies and acute human muscle-protein-synthesis data showing rapamycin blunts the anabolic response to loading.”

Stanfield maintains that there is “real biological tension” between mTORC1 being the master regulator of muscle protein synthesis and sustained mTORC1 inhibition, which is probably responsible for rapamycin’s geroprotective effect. “Timing (‘cycling’) was the hypothesized workaround, but at weekly 6 mg, the pharmacokinetics don’t cooperate,” he said. “Whether longer interdose intervals or much longer treatment durations can strike the right balance is genuinely open. Until we have answers to these questions, my stance since the beginning remains the same: I recommend against off-label rapamycin use. In the meantime, regular exercise remains the unequivocal first line for preserving function in older adults.”

Another co-author, the renowned geroscientist Matt Kaeberlein, disagreed “with the blanket position that rapamycin should never be prescribed off-label.” In a thorough X post, he said: “While we absolutely need better clinical data, there is already a growing body of evidence – along with clinical experience – suggesting benefit in specific contexts. My hypothesis is that the apparent attenuation in functional gains is likely a short-term effect. If the study had extended to 12 months instead of 13 weeks, I would predict the rapamycin group to show improvement.”

“Given that mTOR activation is required for muscle protein synthesis, it’s not surprising that early hypertrophic responses could be blunted,” he added. “But over longer timeframes – especially with intermittent or cycled dosing – it is entirely plausible (and, in my view, likely) that rapamycin could ultimately enhance functional outcomes in older adults.”

Literature

[1] Stanfield, B., Leroux, B., Kaeberlein, M., Jones, J., & Lucas, R. (2026). Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA‐EX‐01 Randomised, Double‐Blind, Placebo‐Controlled Trial. Journal of Cachexia, Sarcopenia and Muscle, 17(2), e70274.

[2] Ruegsegger, G. N., & Booth, F. W. (2018). Health benefits of exercise. Cold Spring Harbor perspectives in medicine, 8(7), a029694.

[3] Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., … & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging cell, 13(3), 468-477.

BioAge Labs, Inc. (Nasdaq: BIOA) (“BioAge” or the “Company”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today reported results from the Phase 1 clinical trial of BGE-102, a potent, structurally novel, orally available, brain-penetrant small molecule NLRP3 inhibitor. The full dataset, which includes a newly announced 60 mg once-daily cohort dosed for 21 days in participants with obesity and elevated inflammation, demonstrates that BGE-102 achieved potential best-in-class reductions in high-sensitivity C-reactive protein (hsCRP) and consistent reductions across multiple inflammatory biomarkers, with a favorable tolerability profile.

Notably, the 60 mg dose achieved hsCRP and other biomarker reductions comparable to the previously reported 120 mg dose. Based on the full Phase 1 dataset, BioAge intends to initiate a dose-ranging Phase 2 cardiovascular risk proof-of-concept trial in the first half of 2026, with data anticipated in the second half of 2026.

“These Phase 1 results position BGE-102 as a potential best-in-class NLRP3 inhibitor, delivering profound hsCRP reductions with a well-tolerated once-daily oral dose,” said Kristen Fortney, Ph.D., CEO and co-founder of BioAge. “These data give us strong conviction to accelerate the program across multiple indications. BGE-102’s potency and tissue penetration make it a potential pipeline in a pill — a single oral therapy to address NLRP3-driven inflammation in cardiovascular, ocular, and CNS diseases. We are rapidly advancing BGE-102 with a Phase 2 dose-ranging trial in cardiovascular risk, a Ph1b/2a proof-of-concept trial in diabetic macular edema, and full investment in CMC, regulatory, and clinical activities to enable Phase 3 initiation in 2027.”

“hsCRP is among the most predictive biomarkers of cardiovascular risk, and targeting inflammation is a clinically validated strategy: prior interventional data for anti-inflammatory therapies demonstrated that reducing hsCRP below 2 mg/L was associated with a 25% reduction in major adverse cardiovascular events,” said Paul Rubin, M.D., Chief Medical Officer of BioAge. “We believe a convenient, well-tolerated oral medicine has broad potential in ASCVD secondary prevention — and potentially in primary prevention as well. These data, demonstrating potent effects across multiple clinically established drivers of cardiovascular risk, suggest that NLRP3 inhibition could have transformational potential, much as statins did for LDL cholesterol decades ago.”

Phase 1 Trial Design

The Phase 1 trial was a randomized, double-blind, placebo-controlled trial in healthy volunteers and participants with obesity, with primary endpoints of pharmacokinetics and safety and exploratory pharmacodynamic endpoints including inflammatory biomarkers. The multiple ascending dose (MAD) portion of the study enrolled healthy volunteers and participants with obesity (BMI 32–42) with elevated systemic inflammation (hsCRP >3 mg/L). The two obese MAD cohorts are reported here: 120 mg once daily for 14 days and 60 mg once daily for 21 days. Prior results from single ascending dose (SAD) and MAD cohorts in healthy volunteers, including pharmacokinetics, brain penetration, and IL-1β suppression data, and additional results from the 120 mg obese MAD cohort, were reported previously.

Biomarker Efficacy in Participants with Obesity and Elevated hsCRP

hsCRP

BGE-102 demonstrated rapid, profound, and sustained reductions in hsCRP at both dose levels, with comparable percent median reductions from baseline:

• 60 mg QD (21-day dosing):
  • 85% reduction at Day 7, 80% at Day 14, 86% at Day 21
  • 87% of participants on active treatment (13/15) achieved normalized hsCRP (<2 mg/L) at Day 21, with 60% (9/15) reaching ≤1 mg/L
• 120 mg QD (14-day dosing):
  • 83% reduction at Day 7, 86% at Day 14
  • 93% of participants on active treatment (13/14) achieved normalized hsCRP (<2 mg/L) at Day 14, with 71% (10/14) reaching ≤1 mg/L

IL-6

Reductions in IL-6, a clinically validated inflammatory mediator of cardiovascular risk, were consistent with hsCRP findings at both dose levels, confirming potent upstream NLRP3 inflammasome inhibition:

• 60 mg QD: 78% reduction at Day 7, 70% at Day 14, 55% at Day 21
• 120 mg QD: 69% reduction at Day 7, 58% at Day 14

Fibrinogen

Reductions in fibrinogen, an established cardiovascular risk marker, were observed at both dose levels:

• 60 mg QD: 20% reduction at Day 7, 19% at Day 14, 23% at Day 21
• 120 mg QD: 24% reduction at Day 7, 30% at Day 14

Additional data from the BGE-102 Phase 1 trial are available in the Company’s corporate presentation, which can be found on the Investors section of the Company’s website.

Safety and Tolerability

BGE-102 was well tolerated across all dose levels evaluated in the Phase 1 study. All treatment-emergent adverse events (TEAEs) were mild to moderate in severity and self-limited, with no dose dependency. There were no serious adverse events, TEAEs leading to discontinuation, or clinically meaningful changes in vital signs, ECGs, or laboratory values.

BGE-102 Planned Development Program

Cardiovascular risk proof-of-concept trial

Based on the complete Phase 1 dataset, BioAge plans to initiate a Phase 2 dose-ranging proof-of-concept trial evaluating BGE-102 in participants at elevated cardiovascular risk in the first half of 2026, with data anticipated in the second half of 2026. Three oral once-daily dose levels will be assessed, with hsCRP as the primary endpoint. The trial is designed to support optimal dose selection for Phase 3. Additional trial design details are available in the Company’s corporate presentation.

Proof-of-concept trial in diabetic macular edema (DME)

BioAge also plans to initiate a Phase 1b/2a proof-of-concept study evaluating BGE-102 in patients with DME in mid-2026, with results anticipated in mid-2027. The trial is designed to demonstrate pharmacodynamic target engagement for BGE-102 in the eye, supporting future development in inflammation-driven retinal diseases. Additional details on the ophthalmology program can be found in the corporate presentation.

More information can be found on the official press release.

The aging and longevity of flies is very dependent on intestinal function. The noted longevity-associated gene INDY acts on intestinal function, for example. Here, researchers report on their investigation of the role of the gut microbiome in INDY-related longevity in flies. As might be expected given the present state of knowledge of the role of the gut microbe in long-term health and aging, there are signs of a contribution. These results are only a first step, however; the gut microbiome is a complex array of different microbial species, and there is a great deal more that might be catalogued in terms of its relationship to genetic associations with longevity in this species.

Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear.

Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiome was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiome and Indy. Indy down-regulation was linked to reduced expression of the JAK/STAT signaling ligands Upd3 and Upd2 in the midgut of young flies, which likely contributes to preserved intestinal stem cell homeostasis. Altogether, our results suggest that Indy reduction impacts microbiome load and composition, which preserves gut homeostasis and extends lifespan through impacts on JAK/STAT signaling pathway.

Link: https://doi.org/10.64898/2026.03.25.714291