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. 2024 Apr 12;16(7):5829-5855.
doi: 10.18632/aging.205743. Epub 2024 Apr 12.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background

Stephen A Banse  1 , E Grace Jackson  1 , Christine A Sedore  1 , Brian Onken  2 , David Hall  3 , Anna Coleman-Hulbert  1 , Phu Huynh  2 , Theo Garrett  3 , Erik Johnson  1 , Girish Harinath  2 , Delaney Inman  3 , Suzhen Guo  2 , Mackenzie Morshead  3 , Jian Xue  2 , Ron Falkowski  2 , Esteban Chen  2 , Christopher Herrera  2 , Allie J Kirsch  1 , Viviana I Perez  4 , Max Guo  4 , Gordon J Lithgow  3 , Monica Driscoll  2 , Patrick C Phillips  1
Affiliations

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background

Stephen A Banse et al. Aging (Albany NY). .

Abstract

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Keywords: aging; compound intervention; genetic diversity; healthspan.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to this study.

Figures

Figure 1
Figure 1
Potential effects of compounds on lifespan and health. A qualitative diagram of possible outcomes for compound effects on lifespan and on healthspan. Lifespan is represented as a change in median survival, while healthspan is represented in the relative rate of decline as compared to the control. The black lines show control, while the blue lines depict slowed aging, and the red lines depict accelerated aging. For health measures, the black dashed line shows the effects of an intervention that is generally stimulatory but does not alter the aging process. Depending on the effect size and direction, each healthspan, compound, and strain combination will fall into one quadrant: lifespan and healthspan extending, healthspan extending, gerospan extending, or toxic. The solid lines between the quadrants indicate no change from the control for a given measure.
Figure 2
Figure 2
Compound effects on oxidative stress resistance. The effect of adult exposure to (A) NP1, (B) propyl gallate, and (C) resveratrol on median survival under oxidative stress conditions, beginning at day 6 and 12 (C. elegans), or day 8 and 16 (C. briggsae) of adulthood. Three strains were tested from each species: C. elegans strains N2, MY16, and JU775 (black text), and C. briggsae AF16, ED3092, and HK104 (gray text). Each point represents the median survival on 40 mM paraquat of an individual trial plate (technical replicate), control (vehicle only – gray) or compound treated (color). The bars represent the mean +/− the standard error of the mean. Biological replicates were completed at the three CITP testing sites (square – Buck Institute, circle – Oregon, and diamond – Rutgers). Asterisks represent p-values from the CPH model such that ****p < 0.0001, ***p < 0.001, **p < 0.01, and *p < 0.05.
Figure 3
Figure 3
Compound effects on thermotolerance. The effect of adult exposure to (A) NP1, (B) propyl gallate, or (C) resveratrol on thermotolerance, specifically median survival at 32°C. Thermotolerance assays were run beginning on day 6 and 12 (C. elegans) or day 8 and 16 (C. briggsae) of adulthood. Three strains were tested from each species: C. elegans strains N2, MY16, and JU775 (black text), and C. briggsae AF16, ED3092, and HK104 (gray text). Each point represents the median survival at 32°C of an individual trial plate (technical replicate), either control (vehicle only – gray), or compound treated (color). The bars represent the mean +/− the standard error of the mean. Biological replicates were completed at the three CITP testing sites (square – Buck Institute, circle – Oregon, and diamond – Rutgers). Asterisks represent p-values from the CPH model such that ****p < 0.0001, ***p < 0.001, **p < 0.01, and *p < 0.05.
Figure 4
Figure 4
Compound effects on CeleST composite swim scores. The effect of adult exposure to NP1, propyl gallate, or resveratrol on overall swimming ability with age in (A) three C. elegans strains (N2, JU775, MY16), and (B) three C. briggsae strains (AF16, JU1348, HK104). Swimming assays were run on days 5, 9, and 12 of adulthood. Bars represent the mean +/− the standard error of the mean. Adjusted swimming score values were normalized to the strain mean value. Two biological replicates were completed at each of the three CITP testing sites. Asterisks represent p-values from the linear mixed model such that ****p < 0.0001, ***p < 0.001, **p < 0.01, and *p < 0.05.
Figure 5
Figure 5
Relative compound effects on health vs. lifespan. Comparing the effect of (A) NP1, (B) propyl gallate, and (C) resveratrol on manual lifespan versus healthspan measures in two Caenorhabditis species (lifespan data from reference [34]). The lifespan effect is the fold change in median lifespan for a strain compared to its untreated control. For health, the relative rate of decline for each strain and compound is compared to the rate of decline for the control. Positive numbers would reflect either lifespan extension or slowed decline in the health measure, while negative numbers would reflect shortened lifespan and accelerated decline in the health measure. Each point represents a strain and health measure combination. Dotted line surrounds expanded box.
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