Drugs that reliably extend lifespan across different genetically varied worm populations

CITP test compounds can be nominated by interested parties following the modalities described on the NIA-hosted CITP Intervention Nomination website (https://www.nia.nih.gov/research/dab/caenorhabditis-intervention-testing-program-citp/citp-intervention-nomination-guide↗). Compound nominators can be individuals, non-profit organizations, academic groups, or businesses. A requirement is that nominators must agree to disclosure of the molecular structure of a new compound tested by the CITP and to CITP publication of results, regardless of positive or negative outcome. Currently, applications are accepted and reviewed on an annual basis.

Applications involve documentation of rationale, preliminary data regarding potential geroprotectant effects, and information on compound chemical properties, availability, and cost. Given the challenges of precise replication of CITP data, CITP has moved away from testing interventions of undefined or variable composition (such as plant extracts). CITP does not test proprietary compounds that cannot be publicly identified immediately after study completion.

Applications are reviewed by members of an expert Access Panel (five scientists from the aging research community plus one investigator from each CITP site who is not the Principal Investigator). The top scored applications are presented to the CITP Steering Committee (made up of four outside experts who are researchers with a broad range of expertise across the aging field; the NIA Project Scientist and the three CITP Principal Investigators) who discuss and prioritize compound entry into testing.

For approved candidates, intervention testing is a collaborative process, and the compound nominator has access to all data as it is generated during the study. Compound sponsors can assist in data analysis and are offered to co-author resulting publications with the CITP.

The public entry path for CITP testing was initiated in 2021. The Access Panel and Steering Committee approved 9 of 12 applications for a total of 16 compounds entering the pipeline through this route. One of the first successful public-suggested compounds is sulforaphane (contained at high levels in broccoli), which can confer ~ 40% median lifespan extension (Sedore et. al., manuscript in preparation). A subset of other nominated compounds appear promising as they move through the current CITP testing pipeline.

We initially focused mainly on compounds that were known to extend C. elegans lab reference strain N2 or compounds with high-profile attention in the anti-aging field, such as rapamycin [13] and metformin [14].

More recently, CITP is focusing on the intersection of datasets of compounds predicted to have the highest chance for engaging conserved aging pathways (doi: https://doi.org/↗ 10.1101/2024.10.23.619838). Predictions are based on the weighted intersection of three datasets: (1) compounds identified by drug/protein interactions to be likely to promote healthy aging transcriptional profiles [15]; (2) compounds identified by machine learning programs to have longevity promotion potential [16]; and (3) compounds identified to promote a “young” transcriptional signature [17]. We prioritized compounds that had not previously been tested for C. elegans longevity (to favor the identification of novel candidates), and we avoided testing compounds with known bactericidal activity (as these might limit the nematode food source to induce a dietary restriction response). This intersection/filtering strategy yielded 16 compounds that entered the CITP pipeline, 5 of which (all-trans-retinoic acid, berberine, fisetin, ritonavir, propranolol) significantly extended median lifespan (doi: https://doi.org/↗ 10.1101/2024.10.23.619838). The high “hit” rate of ~ 30% among these computationally predicted candidates underscores the power of trans-phyla computation combined with in vivo testing approaches to identify potential aging interventions. Furthermore, this approach provides a strong example of how CITP test data can help sort through and rank interventions that merit more detailed study across models. As artificial intelligence prediction power expands, the CITP is poised to rigorously test novel candidate interventions for efficacy in geroprotection.

To accelerate intervention discovery, CITP has also screened through selected chemical libraries for longevity and healthspan, work that is ongoing. In brief, high-throughput screens of two libraries (one containing compounds that target mitochondrial pathways and the other that features neuroprotective compounds) for compounds that confer enhanced survival or thermotolerance (long known to correlate well with longevity) [18] have yielded promising candidate interventions. Preliminary data suggest that novel molecules identified using this approach may exert positive outcomes in CITP testing.

In summary, the CITP casts a broad net of intervention consideration to maximize potential novel compound discovery. Multiple approaches toward efficacious intervention identification have proven successful in the CITP program.

Most published studies of longevity-promoting compounds in C. elegans are conducted using the genetically homogeneous reference lab-adapted strain, designated as N2. Whereas genetic homogeneity offers myriad advantages to mechanistic dissection, genetic homogeneity is likely suboptimal for intervention discovery with translation potential. To more closely mimic a genetically heterogenous target population, the CITP established a representative test set of wild Caenorhabditis strains.

The 22 nematode strains we selected from the three hermaphroditic species of Caenorhabditis were C. elegans (CB4856, ED3040, JU1088, JU1652, JU775, MY16, N2-PD1073 (a frozen ancestral reference line) and QX1211), C. briggsae (AF16, ED3092, HK104, JU1264, JU1348, JU726, NIC20 and QR25), and C. tropicalis (JU1373, JU1630, NIC122, NIC58, QG131 and QG834).

During the course of initial CITP studies, we learned about additional in-lab features of the original test strains (for example, avidity of burrowing deep into the agar), and we felt a need for increased throughput. We refined our workhorse test set to include three C. elegans (N2, MY16, JU775), three C. briggsae (AF16, ED3092, HK104), and three C. tropicalis (JU1630, JU1373, QG834) strains. Over time, we have found C. tropicalis strains to be refractory to the majority of interventions we tested. Therefore, we further streamlined our core test pipeline to increase throughput by focusing first on C. elegans and C. briggsae responses; C. tropicalis is now tested in phase 4 for the most potent interventions we identify (Fig. 2).

We determined the average genome-wide nucleotide diversity (π) within the larger panel and within the core panel of the nine workhorse test strains [19]. We find that the estimated level of genetic diversity among these Caenorhabditis species (within C. elegans (1.2e − 3), C. briggsae (7.5e − 3), and C. tropicalis strains (2.6e − 3)) is higher than that within human populations [20–24] and comparable to that found in mouse populations [25, 26].

In summary, considerable genetic diversity is represented within the core group of C. elegans test strains, and this diversity can match, or surpass, the genetic diversity within mouse and human populations. As such, the CITP workhorse screening panel is optimized to facilitate identification of lifespan-extending chemicals enriched for function in conserved processes shared across genetic backgrounds.

During CITP year 1, the three CITP laboratories worked to accomplish protocol matching, including coordinated purchase and use of same lot number reagents (particularly important for agar), the use of common humidity-controlled incubators for all survival assays (20 °C with 80% humidity, Biological Incubator Model I-36NL, Percival Scientific), and synchronization of autoclaving protocols. The teams agreed on common criteria for scoring animals as dead to finally eliminate variation in survival assay outcomes among labs (see discussion below). To this day, however, the effort requires weekly communication among the CITP site scientists to keep experiments and protocols strictly coordinated. To ensure reproducibility, even very simple assays such as survival of worms on agar in the presence of bacterial food and test compound, can become at least as complex as omic studies.

The CITP adheres strictly to a set of standard operating protocols. Our methods were first described in ref [10]. and can be accessed at Protoc. Exchange https://protocolexchange.researchsquare.com/article/nprot-5341/v1↗. We highlight some details below.

We use test stocks for only 2 months before switching to a fresh stock to prevent genetic drift in wild strains during laboratory use. Animals are maintained continuously on E. coli OP50-1 for at least three generations after starvation, thawing, and/or bacterial decontamination before being used in CITP longevity assays to limit epigenetic changes that might influence longevity assessments.

To assay survival, we first generate synchronized cultures by collecting eggs from 1- to 4-h egg lays from 1- to 2-day-old adults. When the progeny reach day 1 of adult life, we transfer to 35 mm NGM assay plates with or without intervention, with 50 worms placed on each of at least three individual plates (technical replicates). We consider this as a single trial or biological replicate. We transfer animals to fresh pre-warmed plates with or without intervention tightly adhering to a common CITP transfer schedule. Plates include a low dose of FUdR (51 μM) to inhibit reproduction and prevent progeny from over-running the test population. Because of the potential of FuDR to influence longevity outcomes [27–30], we retest longevity promoting compounds in the absence of FuDR as a facet of phase 4 testing.

The CITP most commonly scores survival manually, with any indication of animal response to prodding with a platinum wire as a criterion for viability. We score alive, dead, lost, bagged (extensive internal egg/progeny retention), or extruded intestine. Bagged, lost, and extruded are “censor” categories in which animals are thought to have died of causes other than aging. “Lost” worms may be missing, burrowed, or attached to plate walls. If bacterial contamination is observed, we score all animals on that plate as lost.

The CITP Data Coordinating Center (DCC) provides essential support for data collection, curation, and storage across all three CITP laboratories.

In addition to careful attention to consistent experimental protocols as a key tool for reproducible science, we quickly discovered that a focus on data collection and curation was also critical. Early on, we discovered that different labs recorded the day of death in slightly different ways, which would naturally be a prime driver of among-lab differences. Equally critical for reproducible analysis was the implementation of consistent metadata information management, including seemingly trivial items like capitalization of strain names, date formats, investigator IDs, and more. Small-scale applications of data collection and maintenance via spreadsheets could introduce human error, and our experience quickly drove the development of a database approach, which has undergone several generations of evolution, resulting in a full cloud-based implementation. This is now coupled to a full open-science base analytical pipeline.

Early on, we established access and data collection forms for all research technicians that served to preserve data quality during collection and transmission and to streamline lifespan analysis pipelines: (1) centralized data control and entry allows real-time verification and validation of metadata as well as out-of-range detection on data input and (2) the ability to immediately map new data into our analysis pipelines enables any unexpected experimental outcomes to be detected and looped back into a quality control discussion with the experimental research team. This approach greatly reduces the need for QC editing of the data before final analysis and has allowed us to quickly address any experimental issues that may arise from unseen circumstances, such as variation in thermal control of incubators. The centralized CITP data approach enhances reproducible science by creating an easy path for an identical analytical framework to be applied to every dataset. CITP has published analysis scripts in the hope of aiding outside researchers in implementing similar methods in their own studies. We conduct all statistical analyses on site at the DCC, using well-defined and verified scripts based in the R statistical framework with which we calculate the effects of compounds on longevity using a mixed-model approach, both with a general linear model (GLM) and Cox proportional-hazards models with random effects (ref [10]., Supplementary Software 2).

The CITP Data Portal on the CITP website provides public access to all lifespan data published by the CITP to date. Pulldown menus include lifespan datasets, summary statistics, and lists of tested compounds with searchable data for each strain, from locomotory assessments to transcriptomics. Data can be identified by publication, compound, or strain, with survival plots for specific queries generated. All downloads are provided in a standardized format for public data analysis. Moving forward, CITP plans to leverage our shared experimental protocols to enhance inferences across disparate phenotypes, from locomotory healthspan to transcript analysis via RNAseq, as well as to expand our survivorship analysis to include more sophisticated models of variable mortality rates. In sum, the public CITP Data Portal lays out data and tools for anyone with Internet access to allow mining the data we produce, which we expect will expand the impact of our massive data accumulation: https://citpaging.org/portal↗. The public and comprehensive nature of these datasets also lay the groundwork for educational opportunities, which we are in the process of nurturing.

At the time of CITP inception, a crescendo of commentary focused on a reproducibility crisis in science, a significant concern for the pharmaceutical industry [31–33]. In the invertebrate aging field, controversies over whether intervention outcomes extended, or did not extend, lifespan raged [34–40]. Recognizing the critical importance of reliable data in the aging field, part of the original NIA mandate for the CITP identification of novel anti-aging interventions was that longevity intervention outcomes should be reproduced at distinct sites.

Indeed, CITP data analysis is unique in the invertebrate aging field in that we assess both the effects of compound interventions on individual longevity, and we determine how the variation among several potential sources of that variation is partitioned for interventions that successfully move through the CITP pipeline. Potential sources of variation we have considered are laboratory, species, strain, experimenter, trial, and culture plate. We have also examined possible interactions between laboratory-species and laboratory-strain. This analysis of variation is only possible because of shared experimental approaches and replication across all phases of the work, particularly across strains.

For survival data analysis, we use a mixed-model approach in which “variance-generating” factors are treated as random effects and compounds are treated as fixed effects. R script VarComps.R (ref [10].; Supplemental Software 1) computes the variance component estimates for reproducibility across each of the datasets using hierarchical nested general linear models under a variety of possible error distributions. We examine longevity data for reproducibility at three primary levels: variability in outcomes among labs, variability of outcomes within labs, and sensitivity of outcomes to genetic variation within and among species. Partitioning variation in longevity outcomes to different potential sources of variation in a hierarchical manner using the GLM model has proved quite informative [10].

As noted above, monumental effort was required to bring three different labs to follow the exact protocols for survival studies [41]. In our initial publication partitioning variation for longevity data of 10 compounds in a representative six strains across two species we observed, on average, no differences among labs [10]. We have continued to monitor sources of variance for our studies and have maintained high degree of reproducibility among labs (< 6% of total variance).

In summary, CITP documents a reproducible degree of variation in outcome that transpires similarly at each experimental site. As a team, we produce highly reproducible outcomes, but, despite Herculean efforts toward executing the same experiment at each site, there are still factors that can change the longevity trajectories to contribute roughly on the order of 17% of total variance. Factors that might confer variance include inherently stochastic underlying biology of aging [46] or uncontrollable daily fluctuations in microenvironment (for example, atmospheric pressure, temperature change when incubators are opened, intermittent light exposure, etc.) and elements we cannot easily measure, or even imagine. Our documentation of systematic variation among trials underscores the importance of conducting multiple replicates for survival studies, a point that has been well argued previously in the literature [47].

This is a feature of aging across the animal kingdom, and mobility is an often-cited indicator of human life quality [54]. The CITP quantitates Caenorhabditis swim locomotion as an indicator of locomotory vigor in older age. We chose swim behavior (thrashing in liquid) for focus over simple plate crawling movement because the swim behavior can be analyzed for multiple measurement parameters scorable over a greater dynamic range and for a longer period of adult life than with crawling. For example, good dynamic ranges are found in the wave initiation rate (similar to head thrashes per unit time individuals score manually) and activity index (which measures the area in pixels that the body of the animal covers (“paints”) in two strokes). CITP uses a computational program called CeleST (a C. elegans Swim Test) for analysis of swim behavior, which can score multiple swimmers simultaneously for eight distinct measurement parameters, and offers fully automated tracking and statistical analysis programs [11, 55]. Our statistical team at the CITP Data Center used linear discriminate analysis to weight and combine the eight individual measurements into a single multivariate composite measure of overall swimming ability [45]; this mobility measure, reminiscent of human “frailty index” [56], is currently measured on most potent CITP anti-aging interventions, in phase 4 analyses of compound effects on mobility decline.

On the whole, CITP assessments of locomotory healthspan consequent to intervention treatment generally support that maintained swim vigor is not well correlated with enhanced longevity [45]. On the plus side, we have observed that locomotory healthspan extension can be an outcome of a compound intervention, even in the absence of lifespan extension. For example, CITP found that the anti-diabetes drug metformin increases median survival in three C. elegans strains, but metformin fails to increase C. briggsae median survival. By contrast, metformin prolongs the period of youthful vigor in two of three C. briggsae test strains as well as in all C. elegans strains [14]. We reported a similar outcome for nordihydroguaiaretic acid (NGDA) in C. briggsae [45]. On the other hand, some interventions that extend lifespan in CITP do not markedly alter the decline in swim vigor.

CITP used automated lifespan machines to assess the impact of representative longevity-promoting interventions on oxidative stress (paraquat exposure) and thermotolerance (survival at 32 °C). We tested representative pro-longevity compounds (candidate dietary restriction mimetic NP1, oxidative stress pathway-implicated propyl gallate, and red wine component resveratrol [45], as well as anti-oxidant NDGA and green tea extract, GTE) [13], and we compared the oxidative and thermal stress outcomes with locomotory outcomes. Overall, we find that swimming ability and oxidative stress resistance do not correlate with longevity; thermotolerance correlated better with longevity [45] but could be quite variable [45]. Thus, although we were able to use ALMs to assess animal movement in oxidative and thermal stress studies, the experimental effort required, coupled with the generally poor correlations with longevity, led us to adjust our workflow such that health assessments (primarily locomotion) were moved to phase 4 for interventions that conferred ≥ 20% median lifespan extension.

Separation of lifespan and healthspan outcomes is not uncommon in the aging field [57]. Still, a paucity of intervention screens feature a dedicated focus on healthspan and promising vigor-promoting interventions may be sidelined because of the lack of longevity effect. Given that healthspan-promoting compounds hold huge potential for improving adult life quality [58], focus on healthspan endpoints might be encouraged in the future.

As the CITP increasingly accumulates RNAseq data during adult life interventions, novel health indicators that strongly correlate with longevity (for example, aging clock signatures) may anchor screens for interventions that extend the youthful physicality period of life.

Data enabled us to show that the CITP labs could coordinate efforts to conduct survival assays with outcomes for which minimal variance could be attributed to “among lab” differences. At the same time, we documented ~ 15% of variance of experimental outcome that “reproducibly” transpired within each of the three CITP labs, possibly attributed to unknown factors that influenced outcomes (for example, see baseline longevity for 22 CITP strains across the 3 CITP labs, Fig. 2, Table 1 in Ref.) [10]. Most of the variation in CITP survival outcome can be attributed to genetic differences and individual differences [10]. Data speak to the inherently variable nature of the longevity phenotype and may explain some of the among-lab controversies on intervention outcomes in the aging field [41]. Data also underscore the critical importance of repeat trials.

Over time, the CITP program has been highly cited as a model for considerations of reproducibility challenges in science [59–64].

NIA Scientific Officers Dr. Max Guo and Dr. Tiziana Cogliati established an annual call for compound nomination, provided links to application forms (https://www.nia.nih.gov/research/dab/caenorhabditis-intervention-testing-program-citp/citp-intervention-nomination-guide↗), recruited an expert Access Panel that reviews compound proposals in NIH-grant-review style, and arranged for final approval by the CITP Steering Committee. Approved compounds enter the CITP pipeline as a collaboration with nominators, and data are published regardless of outcome. It is both exciting and gratifying that we have found that some of the nominated compounds confer reproducible longevity. For example, one compound that has emerged via public submission is the broccoli component sulforaphane. We find that sulforaphane can confer significant lifespan (~ 50% median lifespan extension in C. elegans N2) and mobility healthspan extension in the C. elegans genus. Our transcriptomics studies reveal a transcriptional signature response to sulforaphane that reflects increased expression of detoxification gene batteries (Sedore, in preparation).

Intervention survival data for each compound can be easily accessed on our data portal (CITPaging.org). The DCC also manages locomotory (CeleST data and statistics), transcriptomics, and mortality curve analyses. Our centralized database facilitates data collection, quality control, and curation to enable rapid analysis by CITP and by interested outside parties who can access the raw data and the R scripts we use for analysis. The portal for public applications for CITP testing is housed on the NIH CITP website https://www.nia.nih.gov/research/dab/caenorhabditis-intervention-testing-program-citp/citp-intervention-nomination-guide↗.

CITP published extensively detailed protocols and commentary on considerations for best practices toward accomplishing reproducible longevity data [10, 41]. We developed, and made available, R scripts that can be used for survival analysis, attribution of variance, locomotion quantitation, and, more recently, mortality curve analyses. The CITP published user-friendly modifications to automated lifespan machines [12] and discussed considerations their use [49, 48], with the hope that sharing lessons learned and the modifications we implemented will help users adapt ALM technology into their labs.

≥ 20% in at least 1 strain and are efficacious across multiple backgrounds (Table 1). The majority of these compounds are most efficacious in the C. elegans strain set, which might be expected since interventions are commonly selected as plausible candidates due to prior positive influence on C. elegans N2 longevity. The positive outcome in 12 of 69 (excluding several promising compounds still in the pipeline) tests constitutes an ~ 17% success rate for CITP testing over time.

CITP makes a point of emphasizing that negative outcomes should not be interpreted to mean that the compound fails to extend lifespan. Rather, the conclusion to be drawn is that testing of that compound at three sites across a genetically diverse test set and under the CITP standard operating protocols was not effective in promoting enhanced adult survival.

Most interventions work in multiple, but not all, strain backgrounds, an observation that might be attributable to differences in compound uptake or metabolism, genetic background, or test conditions, to name just a few of many possible explanations. As our testing efforts progress, CITP data on transcriptomic and metabolomic responses to compounds across genetically diverse and differentially responding test strains may address potential bases for why certain compounds affect some strains and species differently.

–We reported on interventions that enjoy high profile attention in both the public domain and in the scientific literature.Resveratrol, the renowned red wine component that engages sirtuin activity, extended median lifespan in C. elegans strains (especially JU775, which had ~ 40% relative median extension ) [10]. α-Ketoglutarate, the TCA cycle intermediate that serves as a biosynthetic precursor for glutamate and glutamine, may inhibit TOR [65] and is commonly found in “health food” stores, extended median lifespan > 20% in all three C. elegans test strains, with a striking > 50% increase in strain MY16 [10]. As mentioned above, broccoli component and health supplement sulforaphane was a publicly nominated compound that is highly efficacious (~ 50% median lifespan increase) in C. elegans strains (Sedore, in preparation).

CITP analysis of green tea extract also supported lifespan (significant lifespan extension in five strains across C. elegans and C. briggsae) and locomotory healthspan extension (modest enhancement in multiple test strains) [13]. Given the complexity and variability in extract components, however, the CITP plans to focus on testing interventions with concrete and invariant chemical makeup moving forward.

The biguanide metformin is broadly prescribed to diabetic patients, and data have suggested health benefits that extend beyond balancing of sugar metabolism to include limitations on inflammation and cell senescence. Indeed, exciting trials designed to address metformin as a human anti-aging intervention loom (see the TAME project (Targeting Aging with Metformin) [66]. To model how metformin influences heath and aging outcomes in a genetically diverse population with sequenced genomes, we assayed metformin treatment of the nine CITP test strains [14]. Overall, we documented an impressive and broad health benefit: metformin increases median survival in three C. elegans strains and enhances locomotory capabilities in all three C. elegans and two C. briggsae strains, placing metformin with some of the most potent anti-aging compounds CITP has measured. CITP data thus underscore the potential of metformin to broadly improve older age health and survival in a genetically diverse population.

That said, it is important to point out that metformin was not uniformly efficacious across the Caenorhabditis test set—C. briggsae strains were not long-lived, and metformin was modestly deleterious when fed to C. tropicalis. The metformin/genetic-heterogeneity interface emphasizes that a “one size fits all” outcome might not be anticipated for human metformin intervention and underscores that detailed attention to individual genetic backgrounds might be needed to accurately assess proposed metformin benefits (a consideration for environmental factors as well); a personalized medicine component may be required to maximize health outcomes across a population for this intervention.

CITP did not find strong positive outcomes for some other popular treatments: aspirin, quercetin, and curcumin did not confer longevity benefit [10] despite previously recorded beneficial effects for testing under a different protocol.

The > 30% positive hit rate we found in this study both establishes proof of principle that the computational approach constitutes a promising pipeline strategy and emphasizes how CITP can rapidly generate robust and reproducible data on the growing number of novel candidate compounds that are being published. Expanding similar data mining strategies will enable CITP to identify, and rapidly test for the potential of, novel interventions.

Longevity is just one of many valuable translational outcomes of pro-longevity interventions that extend C. elegans life. Indeed, implications of the geroscience hypothesis (because aging predisposes to many of the diseases of older age, interventions that target the aging process itself will protect against multiple disorders of older age [82]) may be commonly overlooked in the aging field discourse on intervention value. For example, CITP work on ThioT provides a springboard for considering how intervention efficacy might play out for health promotion in higher models. Thioflavin T is an amyloid-binding reagent that can extend lifespan and slow aggregation toxicity in multiple C. elegans models of proteotoxicity, including the expression of human Alzheimer’s disease-implicated neurotoxic peptide Aβ_3–41[83]. CITP documented that ThioT can enhance survival in three C. elegans and two C. briggsae CITP test strains, supporting a broadly efficacious intervention capacity over a genetically diverse test set [10]. The mechanism by which Caenorhabditis aging health is enhanced might operate via proteostasis modulation as it requires a range of regulators of proteostasis for lifespan extension, although ThioT interactions with bacterial food have also been suggested [84]. Whatever the mechanism of action in Caenorhabditis, treatment of older mice with amyloid-binding synthetic molecule 2-hydroxyphenyl-benzoxazole (HBX) (the design of which was based on ThioT) prevented femoral bone loss[72] and protected against ALS pathology [85]. Mouse ITP testing found male median lifespan to be increased by HBX [86]. In other words, a C. elegans influenced intervention in mouse conferred multiple positive health outcomes in aging mice.

Why would an intervention that enhanced longevity in diverse Caenorhabditis promote bone health and brain health in aging mice? From a geroscience hypothesis perspective, conserved pro-longevity modulators identified in C. elegans are predicted to confer unexpected benefits for healthy aging across phyla. A point that may be underappreciated is that invertebrate intervention validation may identify compounds with unexpected benefit in mammalian aging, possibly with segmental or tissue-specific outcomes. CITP data support that attention to such a possibility can play out, at least in aging mice.

Overall, although many compounds are likely to fall out of the invertebrate to mammalian pipeline, those interventions that emerge across models have an enhanced chance of efficacy in humans. Testing against a landscape of genetic heterogeneity reduces concerns regarding genetic background-specific effects and the use of wild-derived strains (i.e., not laboratory adapted) is a powerful argument for high relevance.

The chronic diseases of late life remain the biggest medical, social, and economic challenge of this century. Despite the investment of considerable resources into finding medicines that combat debilitating diseases such as Alzheimer’s and cardiovascular disease, successes are disappointingly few. If indeed aging is a common cause of such diverse conditions, then targeting the aging processes themselves is surely a potential starting point for drug development. Many models are available, including human cell culture, for the discovery of small molecule modulators of aging processes. However, models that encapsulate the entire aging process in an intact living organism are few. The CITP has proven to be an excellent model for the discovery of small drug-like molecules that influence mammalian aging.

Should we expect cures or preventions for chronic disease from the geroscience perspective? Certainly both, but the CITP approach has been to treat animals from early adulthood and is therefore more likely to be a starting point for prevention. One of the challenges of chronic disease therapeutics is the attempt to mitigate symptoms or reverse pathology neglecting etiology. While efforts to reverse or mitigate pathology in diseases such as Alzheimer’s and Parkinson’s must continue, the possibility of prevention may be more realistic. The CITP is well placed to present candidate preventative therapeutic avenues to the biomedical community.