Aging seems inevitable, but have you ever wondered what makes some people age faster than others or why we age at all? Scientists are deeply interested in aging because it is a significant risk factor in many diseases that impact people, such as cancer, diabetes, and Alzheimer’s. If we better understand the biology of aging, we could reduce the prevalence of these age-related disorders. What if I told you that one of the best tools for understanding aging is a tiny transparent roundworm called C. elegans? Yes, you read that right! Studying the mechanisms of aging in C. elegans is helping scientists unlock the secrets of healthy aging in humans. Here we will explore what C. elegans has taught us about aging and how we can apply these findings to humans.
Why study aging with a worm?
C. elegans is a simple yet fascinating organism. It is microscopic, about 1 mm long, and only lives for 2-3 weeks, which speeds up scientists’ ability to research aging. As the worm grows older, it shows many of the same signs of aging as humans, including loss of muscle strength, cognitive decline, and even skin wrinkling. In fact, the first genes that modulate lifespan were identified in C. elegans studies in the late 80s (1) and early 90s (2). Since those original findings, over 3000 more research studies have been published using C. elegans to understand the biological basis of aging.
Hallmarks of Aging
Over the last 30 years, scientists have uncovered that aging is linked to twelve interconnected processes, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These aberrant processes are collectively called the ‘hallmarks of aging’ (3). In addition, C. elegans-based research has shed light on how each hallmark of aging affects lifespan and healthspan. These studies have uncovered conserved biological mechanisms that underlie aging in animals ranging from C. elegans to humans.
The Role of Genes and the Environment on Aging
As we understand more about the biology behind the hallmarks of aging, it has become clear that longevity is the result of the interplay between genetic and environmental factors. The ease of working with the worm allows scientists to carefully control these factors and understand how this interaction modulates lifespan. To date, research in C. elegans has uncovered over 800 genes that affect lifespan (4). Recent studies in the worm have shown that the effects of specific genes on aging are context-dependent, whereby the gene can positively or negatively modulate lifespan based on the environment. Recent examples of this context-dependence have been identified in genes that control immunity (5), epigenetics (6), and food/nutrient-sensing (7).
The Microbiome and Aging
Over the last 20 years, it has been shown that the microbiome, made up of symbiotic bacteria, fungi, and viruses, can profoundly affect human health. Recently, a flurry of studies has suggested that the microbiome can also affect aging (8, 9). C. elegans is a powerful tool for understanding how the microbiome influences lifespan. For example, a screen of over 3000 E. coli gene knockouts revealed 29 mutant bacteria that increased the lifespan of their C. elegans host (10). Five of these gene knockouts led to increased colanic acid production, which improved mitochondrial function in older worms. Importantly, colanic acid seemed to have a similar effect on mitochondria in rodent cells, showing the conservation of its effect from worms to mammals. Another recent study has shown that number of Bifidobacterium adolescentis bacteria in the human gut decreases with age (11). When this bacterial strain is put into the C. elegans gut, it increases lifespan by decreasing the oxidative stress experienced by the host animals. This bacterial strain also reduced frailty in a mouse model of premature aging by modulating oxidative stress, again showing the conservation of function from worms to mammals. Thus, C. elegans could help identify microbial products that promote healthy aging across species, including humans.
NemaLife’s Mission to Accelerate Healthy Aging Research
NemaLife’s organism-on-chip platform combines the advantages of C. elegans as a model organism for aging with our proprietary AI-enabled microfluidic imaging system to supercharge longevity research. Our technology reduces the experimental labor needs and data analysis times associated with longevity studies in the worm. For example, we recently conducted an NIH-funded study to identify novel compounds that could be developed into therapeutics for age-related neurodegenerative diseases like Alzheimer’s. As part of this study, we were able to screen a select library of 250 compounds against two different worm models of Alzheimer’s disease and identify 32 hits that improved survival in less than three months. In addition, we have also partnered with many companies to examine whether their functional food ingredients or bioactives can promote healthy aging.
The nematode C. elegans has played a pivotal role in shaping our understanding of the biology of aging over the last three decades. The short lifespan of the worm, plus the ease of working with it, enables scientists to conduct large-scale studies of the biology of aging that would be impossible in mammals. These insights into aging provide a roadmap that will help scientists understand and treat age-related conditions, proving that this microscopic worm has an oversized effect on human health. NemaLife is accelerating the speed of discovery and compressing the timeline for product innovation by creating a platform that enables efficient and scalable in vivo screening.
Citations
1. Friedman DB, Johnson TE. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics. 1988;118(1):75-86. doi: 10.1093/genetics/118.1.75. PubMed PMID: 8608934; PMCID: PMC1203268.
2. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366(6454):461-4. doi: 10.1038/366461a0 PMID - 8247153.
4. GenAge Database of Ageing-Related Genes [Internet] [cited 05/08/2023]. Available from: https://genomics.senescence.info/genes/search.php?organism=Caenorhabditis+elegans&show=5.
6. Guillermo ARR, Chocian K, Gavriilidis G, Vandamme J, Salcini AE, Mellor J, Woollard A. H3K27 modifiers regulate lifespan in C. elegans in a context-dependent manner. BMC Biol. 2021;19(1):59. Epub 20210325. doi: 10.1186/s12915-021-00984-8. PubMed PMID: 33766022; PMCID: PMC7995591.