Organismal Models and the Hallmarks of Aging
Summary
Longevity research has grown rapidly over the last few decades.
One aspect of research is different organismal models used for testing.
While mice remain the gold standard for model choice, other organisms have their own strengths.
Another important part of research is identifying what to measure.
The development of "Hallmarks of Aging" (opens in a new tab) helped with this.
These hallmarks have cycled in popularity.
They were initially dominated by genomic instability due to DNA damage theories like the Free Radical Theory of Aging (opens in a new tab).
Now, research distribution has evened out due to advances in our knowledge of genetic (opens in a new tab), epigenetic (opens in a new tab), and autophagic (opens in a new tab) processes.
Each of these hallmarks has been studied in different organisms, some more often than others.
| Model Organism | Most Cited Hallmark |
|---|---|
| Mouse | Genomic Instability |
| Zebrafish | Genomic Instability |
| Fruit Fly | Disabled Macroautophagy |
| C. Elegans | Disabled Macroautophagy |
| Yeast | Genomic Instability |
Deciphering these model-specific hallmark relationships may be key to unlocking the mechanisms of human aging itself.
Organismal Model Tradeoffs
| Characteristic | Mouse 🐁 | Zebrafish 🐟 | Fruit Fly 🪰 | C. elegans 🪱 | Yeast 🧫 |
|---|---|---|---|---|---|
| Typical Lifespan | ~2 years | ~3 years | ~2 months | ~2 weeks | ~2 weeks |
| Genetic Manipulation Ease | Moderate | High | High | High | Very High |
| Reproductive Cycle | Slow | Moderate | Fast | Fast | Very fast |
| Maintenance Cost | High | Moderate | Moderate | Low | Very low |
| Genome Size | ~2.7 billion bp | ~1.7 billion bp | ~165 million bp | ~100 million bp | ~12 million bp |
| Genetic Similarity to Humans | ~85% | ~70% | ~60% | ~35% | ~20% |
| Genetic Conservation of Aging Pathways | Very High | High | High | High | Moderate |
| Research Infrastructure & Tools | Extensive | Moderate | Extensive | Extensive | Extensive |
| Ease of Environmental Control | Moderate | High | High | Very high | High |
| Ethical Considerations | Moderate | Moderate | Minimal | Minimal | Minimal |
Mus Musculus (House Mouse)
| Pros | Cons |
|---|---|
| High Genetic Homology | High Maintenance Costs |
| Vertebrate Model | Ethical Considerations |
| Extensive Genetic Tools | Inbred Strains Limitations |
| Effective Disease Models | Longer Lifespan |
| Multiple Aging Strains | Premature Aging Confounds Epigenetics, Developmental Delays in Some Models |
| Existing Aging Models | Developmental Delays in Some Models |
PubMed Citations
76,300
Impactful Studies
- Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart (opens in a new tab)
- Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue (opens in a new tab)
- Longevity, stress response, and cancer in aging telomerase-deficient mice (opens in a new tab)
Citations by Primary Hallmarks of Aging
Danio Rerio (Zebrafish)
| Pros | Cons |
|---|---|
| Vertebrate Model | Less Established Model |
| Short Lifespan | Higher Maintenance Costs |
| Genetically Tractable | Ethical Considerations |
| Transparent Embryos | |
| High Reproductive Rate |
PubMed Citations
1,345
Impactful Studies
- Heart Regeneration in Zebrafish (opens in a new tab)
- Modeling neurodegeneration in zebrafish (opens in a new tab)
- Development and maturation of the immune system in zebrafish, Danio rerio: a gene expression profiling, in situ hybridization and immunological study (opens in a new tab)
Citations by Primary Hallmarks of Aging
Drosophila melanogaster (Fruit Fly)
| Pros | Cons |
|---|---|
| Genetically Tractable | Cannot Fully Model Human Aging |
| Short Lifespan | Low DNA Methylation |
| Existing Epigenetic Studies | Invertebrate Limitations |
| Post-Mitotic Cells | |
| Cost-Effective | |
| Extensive Genetic Tools | |
| Minimal Ethical Concerns |
PubMed Citations
3,874
Impactful Studies
- Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster (opens in a new tab)
- Absence of effects of Sir2 over-expression on lifespan in C. elegans and Drosophila (opens in a new tab)
- Age-associated decline in mitochondrial respiration and electron transport in Drosophila melanogaster (opens in a new tab)
Citations by Primary Hallmarks of Aging
Caenorhabditis Elegans (Nematode Worm)
| Pros | Cons |
|---|---|
| Genetically Tractable | Cannot Fully Model Human Aging |
| Short Lifespan | Limited Genetic Homology |
| Post-Mitotic Cells | Simplistic Anatomy |
| Cost-Effective | |
| Rapid Reproduction | |
| Minimal Ethical Concerns |
PubMed Citations
5,787
Impactful Studies
- A C. elegans mutant that lives twice as long as wild type (opens in a new tab)
- Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism (opens in a new tab)
- Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans (opens in a new tab)
Citations by Primary Hallmarks of Aging
Saccharomyces Cerevisiae (Yeast)
| Pros | Cons |
|---|---|
| Genetically Tractable | Limited Human Aging Modeling |
| Extensive Genetic Tools | Unicellular Limitations |
| Short Lifespan | Low Genetic Similarity |
| Dual Aging Pathways | |
| Cost-Effective | |
| Minimal Ethical Concerns |
PubMed Citations
5,618
Impactful Studies
- The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms (opens in a new tab)
- Extension of chronological life span in yeast by decreased TOR pathway signaling (opens in a new tab)
- Regulation of longevity and stress resistance by Sch9 in yeast (opens in a new tab)
Citations by Primary Hallmarks of Aging
Boring Stuff
Background
The most popular organismal models in longevity research based on number of citations are:
- Mus Musculus (House Mouse)
- Caenorhabditis Elegans (Nematode Worm)
- Saccharomyces cerevisiae (Yeast)
- Drosophila melanogaster (Fruit Fly)
- Danio Rerio (Zebrafish)
The five primary hallmarks of aging according to Lopez-Otin, Blasco et al., 2023 (opens in a new tab) are:
- Genomic Instability
- Telomere Attrition
- Epigenetic Alterations
- Loss of Proteostasis
- Disabled Macroautophagy
Methods
The following PubMed search queries were used to find citations for each hallmark and model organism:
Hallmarks:
-
Genomic instability: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Genomic Instability"[MeSH] OR "genomic instability" OR "DNA damage" OR "chromosomal instability" OR "mutation accumulation" OR "DNA repair defects" OR "double-strand breaks" OR "microsatellite instability")
-
Telomere attrition: ("Telomere Attrition"[MeSH] OR "telomere attrition") OR ("Telomere"[MeSH] OR telomere) AND ("telomere shortening" OR "telomere dysfunction" OR "telomere maintenance" OR "telomerase activity" OR "telomere length" OR "alternative lengthening of telomeres" OR "ALT" OR "telomere-binding proteins")
-
Epigenetic alterations: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Epigenetic Alterations"[MeSH] OR "epigenetic alterations" OR "epigenetic changes" OR "DNA methylation" OR "DNA hydroxymethylation" OR "histone modification" OR "chromatin remodeling" OR "chromatin accessibility" OR "nucleosome positioning" OR "epigenetic drift" OR "non-coding RNA" OR "histone acetylation" OR "histone methylation" OR "epigenetic regulation")
-
Disabled macroautophagy: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Autophagy, Macro"[MeSH] OR "disabled macroautophagy" OR macroautophagy OR autophagy OR "selective autophagy" OR mitophagy)
-
Loss of proteostasis: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Loss of Proteostasis"[MeSH] OR "loss of proteostasis" OR proteostasis OR "protein folding" OR "molecular chaperones" OR "ubiquitin-proteasome system" OR UPS)
Model Organisms:
-
Mouse: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Mus musculus"[MeSH] OR mouse)
-
C. elegans: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Caenorhabditis elegans"[MeSH] OR nematode OR nematodes)
-
Yeast: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Saccharomyces cerevisiae"[MeSH] OR yeast)
-
Fruit fly: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Drosophila melanogaster"[MeSH] OR "fruit fly")
-
Zebrafish: ("Longevity"[MeSH] OR "Aging"[MeSH] OR longevity OR aging OR "lifespan extension") AND ("Danio rerio" OR "zebrafish")