Aging Mechanisms in Caenorhabditis elegans

Introduction

Aging is a complex biological process involving genetic and molecular changes that lead to progressive decline in function. Model organisms like the nematode Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae have been instrumental in uncovering conserved aging mechanisms. C. elegans is a multicellular eukaryote with a short lifespan (~2–3 weeks) and well-mapped genetics, making it ideal for studying organismal aging​ frontiersin.org​ frontiersin.org. Yeast, as a single-celled eukaryote, has provided fundamental insights into cellular aging pathways applicable to higher organisms​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. This report reviews the known genetic and molecular mechanisms of aging in C. elegans—focusing on pathways regulating lifespan, stress resistance, metabolic control, and cellular senescence—and compares them to aging pathways in S. cerevisiae. Key longevity genes (e.g. daf-2, daf-16 in worms and SIR2 in yeast) and their associated pathways are highlighted, along with similarities and differences that shed light on the evolution of aging regulation.

Genetic and Molecular Mechanisms of Aging in C. elegans

Caenorhabditis elegans exhibits clear aging phenotypes (decline in motility, fertility, and tissue integrity) and has been pivotal in identifying “gerontogenes” – genes that modulate lifespan. Many C. elegans mutants with extended lifespan were found to affect specific signaling pathways, revealing that aging is not merely passive wear-and-tear but is under genetic control​ frontiersin.org​ frontiersin.org. Major longevity pathways in the worm include the insulin/IGF-1 signaling cascade, dietary restriction responses, stress-response pathways, and mitochondrial metabolic pathways. Worm somatic cells are largely post-mitotic (non-dividing) in adulthood, so aging manifests as functional decline and damage accumulation rather than replicative senescence​ frontiersin.org. Below we outline key mechanisms:

Insulin/IGF-1 Signaling (IIS) Pathway

One of the most studied pathways in C. elegans aging is the insulin/IGF-1 signaling (IIS) pathway​ frontiersin.org. The IIS pathway in worms involves three core genes: daf-2, age-1, and daf-16. daf-2 encodes the insulin/IGF-1 receptor homolog, and age-1 encodes the p110 catalytic subunit of PI3K​ frontiersin.org. When IIS is active (e.g. under plentiful nutrients and growth conditions), DAF-2 signaling through AGE-1 (PI3K) and downstream kinases (PDK-1, AKT-1/AKT-2, SGK-1) keeps the FOXO transcription factor DAF-16 phosphorylated and sequestered in the cytoplasm​ frontiersin.org. Reduced IIS (as in daf-2 or age-1 loss-of-function mutants) causes a cascade of events: AKT kinase activity drops, allowing DAF-16 to dephosphorylate and translocate into the nucleus, where it activates a broad longevity program​ frontiersin.org. DAF-16 induces genes that promote stress resistance (e.g. antioxidant and heat-shock proteins), antimicrobial defense, metabolic adjustments, and cellular maintenance, ultimately extending lifespan​ frontiersin.org frontiersin.org. In fact, mutations in daf-2 or age-1 produce some of the largest lifespan extensions observed in C. elegans, roughly doubling longevity in certain cases​ frontiersin.org​ frontiersin.org. This extension strictly requires daf-16 – if daf-16 is knocked out, the longevity of daf-2 mutants is lost​ frontiersin.org​ frontiersin.org, showing that DAF-16 is the central effector of IIS-mediated lifespan control.

Reduced IIS not only extends lifespan but also enhances stress resistance. Long-lived daf-2 mutants show increased ability to withstand heat, oxidative stress, and pathogens​ frontiersin.org. This is because DAF-16 (FOXO) activates stress-protective mechanisms such as detoxification enzymes and molecular chaperones​ frontiersin.org​ frontiersin.org. Notably, the IIS pathway also has a developmental role: in young worms, low IIS can trigger entry into the dauer state – a diapause larval stage that is long-lived and stress-resistant​ frontiersin.org. DAF-16 activation is required for dauer formation, linking developmental plasticity to longevity. Other transcription factors work alongside DAF-16 in IIS longevity control. For example, the NF-E2-like factor SKN-1 (worm ortholog of NRF2) functions in parallel to DAF-16: under low IIS, SKN-1 enhances expression of detoxification genes and even extracellular matrix components to maintain organismal integrity​ frontiersin.org​ frontiersin.org. While SKN-1 improves stress resistance, some evidence suggests DAF-16 and SKN-1 coordinately regulate longevity, with complex cross-talk between their pathways​ frontiersin.org​ frontiersin.org. Another IIS-responsive factor is the heat-shock factor HSF-1, which is discussed later as a major regulator of proteostasis and longevity. Together, these factors illustrate how IIS reduction shifts the organism from a growth/reproduction mode to a somatic maintenance mode conducive to longevity.

Figure 1: Major longevity pathways in C. elegans. The insulin/IGF-1 (IIS) pathway signals through DAF-2 (insulin/IGF receptor) and AGE-1 (PI3K), which via kinases (AKT-1/2, SGK) inhibit the FOXO transcription factor DAF-16. Under low IIS (e.g., reduced insulin-like peptide signaling), DAF-16 enters the nucleus to activate genes that enhance stress protection and repair​ frontiersin.org. Parallel pathways modulate aging: dietary restriction (DR) triggers AMPK activation, which phosphorylates factors (e.g., CREB, FOXO) and overlaps with sirtuin (SIRT1) effects; low amino acid levels inhibit mTOR signaling, which in turn can induce autophagy via HLH-30 (TFEB)​ frontiersin.org​ frontiersin.org. Transcription factors SKN-1 (NRF2) and PHA-4 (FOXA) are additional longevity regulators under low IIS or DR conditions​ frontiersin.org​ frontiersin.org. Green arrows indicate activation, red bars indicate inhibition.​ frontiersin.org​ frontiersin.org

Dietary Restriction and Energy-Sensing Pathways

Dietary restriction (DR) – reduced food intake without malnutrition – robustly extends lifespan in C. elegans, as in many species​ frontiersin.org​ frontiersin.org. Worms subjected to DR (for example, using eat-2 mutants that have reduced feeding) live longer and are protected from age-related pathologies​ frontiersin.org​ frontiersin.org. DR does not extend life through a single linear pathway but engages multiple mechanisms. Two hypotheses in worms are that DR works by (1) lowering IIS activity and/or (2) lowering overall metabolic rate​ frontiersin.org. Genetic analyses indicate DR-induced longevity requires specific transcription factors like PHA-4, a FOXA ortholog. PHA-4 is necessary for lifespan extension in eat-2 DR worms and functions in a pathway distinct from IIS​ frontiersin.org. If IIS is reduced via daf-2 mutation, PHA-4 is not required for that longevity, indicating DR and IIS have at least partly separate outputs​ frontiersin.org. PHA-4/FOXA, however, is required for lifespan extension by inhibiting the mTOR pathway (discussed below), suggesting PHA-4 integrates nutrient signals to promote longevity​ frontiersin.org.

Energy stress from limited diet also activates cellular energy sensors such as AMP-activated protein kinase (AMPK). In worms, AMPK is encoded by aak-2, and it links low energy status to aging modulation​ frontiersin.org​ frontiersin.org. Overexpression of AMPK (AAK-2) extends C. elegans lifespan​ frontiersin.org. When cellular AMP levels rise (energy deficit), AMPK phosphorylates targets that shift metabolism towards maintenance: for instance, AMPK can directly phosphorylate DAF-16/FOXO and enhance its activity​ frontiersin.org​ frontiersin.org. Activated AMPK also influences other regulators like CREB and SIR-2.1 (a sirtuin deacetylase, homolog of mammalian SIRT1)​ frontiersin.org. The longevity effect of AMPK in worms overlaps with IIS reduction – aak-2 requires DAF-16 to fully promote longevity, indicating that low energy signaling feeds into the DAF-16 network​ frontiersin.org​ frontiersin.org. In essence, AMPK acts as a metabolic checkpoint that triggers life-extending programs when nutrients are scarce, mirroring its conserved role in mammals​ frontiersin.org​ frontiersin.org.

Another major nutrient-sensing pathway is the mechanistic Target of Rapamycin (mTOR) pathway. mTOR is a conserved kinase that promotes growth and protein synthesis in nutrient-rich conditions. C. elegans has an mTOR homolog (let-363) and an S6 Kinase (rsks-1) among other components. Inhibition of mTOR (for instance by mutation or the drug rapamycin) significantly prolongs worm lifespan​ frontiersin.org. mTOR signaling is largely distinct from IIS, as worms with reduced IIS and reduced mTOR have an additive or synergistic increase in longevity​ frontiersin.org​ frontiersin.org. One shared downstream mechanism is autophagy, the cellular recycling process. Both IIS reduction and mTOR inhibition promote autophagy, and autophagy is required for their lifespan extension effects​ frontiersin.org​ frontiersin.org. Specifically, low mTOR activity frees the transcription factor HLH-30 (worm TFEB) to enter the nucleus and upregulate genes for autophagy and lysosomal function​ frontiersin.org. HLH-30/TFEB has been shown to work in concert with DAF-16 to enhance longevity, highlighting that proteostasis (protein/organelle quality control) is a linchpin of longevity pathways​ frontiersin.org. mTOR also impacts metabolism by regulating mitochondrial gene expression via co-factors like PGC-1α and YY1 (identified in mammals)​ frontiersin.org. In worms, reducing mTOR or altering amino acid levels (e.g. lower methionine) shifts metabolism and can extend lifespan​ frontiersin.org​ frontiersin.org. Overall, dietary restriction triggers a web of nutrient-sensing adjustments – decreased IIS, increased AMPK, decreased mTOR – that converge on activating maintenance mechanisms (like DAF-16, PHA-4, autophagy). This yields enhanced stress resistance and longevity rather than growth. Notably, these pathways are conserved: reducing IIS or mTOR, or activating AMPK, slows aging in organisms from worms to mammals​ frontiersin.org​ frontiersin.org.

Stress Resistance and Proteostasis

Long-lived C. elegans typically exhibit heightened resistance to stress, thanks to activation of stress response genes. Two transcription factors are paramount here: DAF-16 (already discussed) and HSF-1 (Heat Shock Factor 1). HSF-1 orchestrates the heat-shock response by inducing molecular chaperones (heat shock proteins) that prevent protein aggregation. It also has a direct role in longevity. In C. elegans, HSF-1 is required for the extended lifespan of IIS mutants – knocking down hsf-1 shortens lifespan to normal levels, epistatic to daf-2 pmc.ncbi.nlm.nih.gov. HSF-1 and DAF-16 function in overlapping pathways to promote longevity, as reducing HSF-1 and DAF-16 together is not more detrimental than either alone​ pmc.ncbi.nlm.nih.gov. Overexpressing hsf-1 in worms is sufficient to extend lifespan (~20% extension)​ pmc.ncbi.nlm.nih.gov. HSF-1 overexpression leads to upregulation of chaperones like HSP-70, enhancing proteostasis capacity in somatic tissues​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Conversely, inhibiting HSF-1 accelerates aging and protein damage. Thus, HSF-1 acts as a pro-longevity “guardian of the proteome,” maintaining protein folding and preventing toxic aggregates that accumulate with age​ nature.com​ pmc.ncbi.nlm.nih.gov. In summary, C. elegans longevity is tightly linked to robust proteostasis: mutants that live long tend to express more chaperones, better protein degradation systems, and effective unfolded protein responses, all coordinated by factors like HSF-1 and DAF-16.

Another critical stress-response factor is SKN-1, which regulates phase II detoxification enzymes and antioxidant proteins (analogous to NRF2 in mammals). Under normal conditions, IIS keeps SKN-1 in check, but when IIS is low, SKN-1 becomes active especially in the intestine​ frontiersin.org. SKN-1 helps worms mitigate oxidative stress by inducing genes that neutralize reactive oxygen species (ROS) and remove xenobiotics​ frontiersin.org​ frontiersin.org. Interestingly, SKN-1 also increases expression of collagens and extracellular matrix components under low IIS​ frontiersin.org, suggesting it may reinforce structural integrity of tissues during aging. While SKN-1 contributes to stress resistance, its exact role in longevity is complex; some studies indicate that maximal lifespan extension by IIS mutants can occur even if certain SKN-1 functions are compromised​ frontiersin.org. Nonetheless, SKN-1 is part of the pro-longevity network and illustrates that enhanced oxidative stress resistance is a hallmark of many worm longevity mutants. Indeed, daf-2 and daf-16 mutants show altered expression of antioxidant enzymes (like superoxide dismutases, peroxiredoxins), and long-lived worms often survive oxidative challenges better than wild type​ frontiersin.org​ frontiersin.org. This supports the idea that aging involves cumulative damage (such as oxidative damage) and that boosting stress defenses can slow aging.

Proteostasis (protein homeostasis) encompasses not only chaperones but also protein degradation systems. Autophagy, mentioned above, is crucial for removing damaged organelles and misfolded proteins in aging cells. In C. elegans, autophagy genes are required for lifespan extension in several longevity models (e.g., daf-2 mutants require autophagy for full lifespan extension)​ frontiersin.org​ frontiersin.org. The TFEB homolog HLH-30 is activated in long-lived mutants and promotes autophagic flux​ frontiersin.org. The proteasome, which degrades ubiquitinated proteins, is another component; while not as extensively studied in worms as in yeast, enhancing proteasome activity has been linked to longevity in some contexts​ pmc.ncbi.nlm.nih.gov. Worms accumulate misfolded proteins with age, visible as aggregates or increased autofluorescence, so maintaining protein quality is vital to delay aging​ jci.org​ jci.org.

In addition to the cytoplasmic proteostasis, organelle-specific stress responses contribute to longevity. The unfolded protein response of the endoplasmic reticulum (UPR^ER) and of mitochondria (UPR^mt) are activated in some long-lived worms. For example, overexpressing xbp-1 (a UPR^ER transcription factor) extends worm lifespan by improving protein-folding capacity in the ER​ nature.com. Mild mitochondrial stress can activate UPR^mt, which induces protective mitochondrial chaperones; this has been observed to extend lifespan in certain mitochondrial mutants (discussed next). Overall, C. elegans demonstrates that an organism’s longevity is strongly determined by its ability to resist and repair stress-induced damage. Longevity-assurance pathways mobilize a network of stress responses (HSF-1, SKN-1, UPR, autophagy), allowing the animal to maintain cellular integrity for longer frontiersin.org​ frontiersin.org.

Mitochondrial Metabolism and Aging

Mitochondria are both energy generators and sources of metabolic waste (like ROS), making them pivotal in aging. Paradoxically, in C. elegans, several mutations that disrupt mitochondrial function extend lifespan. These include mutations in genes like clk-1 (involved in CoQ biosynthesis), isp-1 (Complex III subunit), and nuo-6 (Complex I subunit). Such mutants often develop slowly and have lower respiration rates, but live longer than wild type. The prevailing explanation is a hormetic response: mild impairment of the electron transport chain leads to a moderate increase in ROS that activates stress defenses, ultimately lengthening lifespan – a concept known as mitohormesis pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. For instance, knockdown of cyc-2.1 (a cytochrome chain gene) was found to extend worm lifespan by triggering the mitochondrial unfolded protein response (UPR^mt) and AMPK, improving mitochondrial quality control​ frontiersin.org​ frontiersin.org. Long-lived mitochondrial mutants in worms typically require stress-response factors (like DAF-16, SKN-1, or UPR^mt components) to realize their full longevity, underscoring that it’s the activation of protective pathways – not the damage per se – that extends life.

Metabolic rate and fuel usage also change with age. C. elegans stores fat in intestinal cells, and fat metabolism genes can influence lifespan. For example, a deficiency in germline cells (see below) causes fat to be redistributed and metabolized in a way that supports longevity. Additionally, signaling through DAF-16 and SKN-1 can induce expression of enzymes that alter metabolic flux (e.g., enhancing beta-oxidation of fatty acids or glyoxylate cycle activity), creating an energetic state favorable for longevity​ frontiersin.org​ frontiersin.org. Another transcription factor, NRF-1 (nuclear respiratory factor 1, called W02A2.6 in worms), and the hypoxia-inducible factor HIF-1 have been implicated in coordinating metabolism under low-energy or low-oxygen conditions to extend lifespan in certain contexts​ frontiersin.org​ frontiersin.org.

In summary, mitochondrial signals can modulate aging in C. elegans. A slight dysfunction can induce a compensatory survival response (involving UPR^mt, antioxidants, and metabolic shift) that slows aging. However, severe mitochondrial dysfunction shortens lifespan, indicating there is an optimal balance. The finding that some mitochondrial stress can lengthen life has parallels in other species and reveals conserved pathways of energy sensing and damage mitigation at the organelle level.

Reproductive Signals and Other Longevity Factors

In multicellular organisms, reproductive status and signals can influence aging. C. elegans provided a breakthrough observation: removing the germline precursor cells (for example, via laser ablation or a mutation in the germline proliferative factor GLP-1/Notch) extends the lifespan of the adult worm. Germline-less worms live significantly longer, and this requires DAF-16 activity in the somatic tissues​ frontiersin.org​ frontiersin.org. The model is that germ cells (or the process of reproduction) emit signals that accelerate aging of the soma, possibly to maximize reproductive success earlier in life (a disposable soma concept). In the absence of a germline, the somatic gonad produces steroid-like hormones (dafachronic acids) that activate the nuclear hormone receptor DAF-12, which in turn cooperates with DAF-16 to extend lifespan​ frontiersin.org​ frontiersin.org. Thus, aging in C. elegans is not only cell-autonomous but also subject to endocrine regulation: signals from reproductive tissues modulate the whole organism’s aging rate. This is a unique aspect of multicellular aging not present in yeast (where each cell is essentially its own “organism”). It highlights how evolution has tied aging to developmental and reproductive programs.

Epigenetic regulation is another layer influencing worm aging. Chromatin modifiers can alter lifespan without changing DNA sequence. For example, the H3K4me3 histone methyltransferase complex (SET/MLL complex, called COMPASS in worms) has been implicated in aging: worms with reduced H3K4 trimethylation live longer​ frontiersin.org​ frontiersin.org. Mutations in components of this complex (sometimes termed “Trithorax-group” proteins) extend lifespan and intriguingly, the effect can be transmitted to descendants for a few generations​ frontiersin.org​ frontiersin.org. This suggests that chromatin state (heritable gene expression patterns) can influence longevity. The H3K4me3 effect seems to act via the mTOR pathway, specifically through the S6K/RSKS-1 output, linking chromatin modification to nutrient signaling​ frontiersin.org. Other chromatin factors, like the H3K27 demethylase UTX-1, can shorten lifespan by activating IIS genes (e.g., utx-1 loss extends life by allowing DAF-16 to remain active)​ frontiersin.org​ frontiersin.org. Additionally, the sirtuin sir-2.1 in worms (homolog of yeast SIR2) is a protein deacetylase that epigenetically silences genes; extra copies of sir-2.1 were reported to extend worm lifespan, although its role is context-dependent​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. sir-2.1 may promote longevity by deacetylating histones or targets like DAF-16, thereby affecting gene expression profiles that favor stress resistance and survival​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov.

Finally, various non-coding RNAs contribute to worm aging regulation. For instance, a long non-coding RNA tts-1 is upregulated in daf-2 mutants and appears to extend lifespan by downregulating ribosomal protein genes (effectively reducing protein synthesis)​ frontiersin.org. Lower protein synthesis can reduce energy expenditure and proteotoxic stress, aligning with the concept that a slower metabolic rate can extend life​ frontiersin.org. MicroRNAs have also been identified that change with age and can modulate lifespan by fine-tuning gene expression post-transcriptionally.

In conclusion, C. elegans aging is controlled by an interconnected network of genetic pathways: nutrient-sensing (IIS, AMPK, mTOR, dietary restriction), stress response (FOXO/DAF-16, HSF-1, SKN-1, autophagy, UPR), metabolic adaptation (mitochondrial function, energy balance), and reproductive signaling (germline, steroid hormones). These pathways do not act in isolation; they often converge on common outputs (like enhanced proteostasis and stress resistance). The worm has taught us that aging rate is malleable: tweaking a single gene like daf-2 or age-1 can dramatically slow aging​ frontiersin.org​ frontiersin.org. Many of these mechanisms have parallels in other organisms, indicating evolutionarily conserved aging programs.

Aging Mechanisms in Saccharomyces cerevisiae (Yeast)

Saccharomyces cerevisiae provides a simpler, single-celled model to study fundamental aging processes. Yeast has two primary aging paradigms: replicative lifespan (RLS) – the number of daughter cells a mother cell can produce before senescence – and chronological lifespan (CLS) – the duration a non-dividing cell survives in a quiescent, stationary phase​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. These correspond conceptually to aging of dividing cells (like stem cells) and aging of post-mitotic cells, respectively, in higher eukaryotes. Research in yeast has uncovered key genes and pathways that modulate aging, many of which are conserved. Below we summarize yeast aging mechanisms, noting similarities to the worm pathways discussed.

Nutrient Sensing and Longevity in Yeast

Yeast cells adjust their growth and stress responses based on nutrient availability, and this has a direct impact on lifespan. Two major pro-aging signaling pathways in yeast are analogous to IIS and mTOR in worms: (1) the Tor/S6K pathway and (2) the Ras/adenylate cyclase/PKA pathway pmc.ncbi.nlm.nih.gov. Both pathways sense nutrients and promote growth and reproduction at the expense of maintenance.

• TOR/S6K Pathway: Yeast has two TOR kinases (TOR1, TOR2) that form TORC1, which, when nutrients (especially amino acids) are abundant, activates processes for protein synthesis and cell growth. TORC1 in yeast activates the S6 kinase homolog Sch9 (functional analog of worm RSKS-1/S6K)​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. Reduced TOR signaling—achieved by caloric restriction, TOR-inhibiting drugs like rapamycin, or deletion of TOR1/Sch9—extends lifespan. In chronological aging assays, tor1Δ or sch9Δ yeast can survive much longer in stationary phase than wild type​pmc.ncbi.nlm.nih.gov. Mechanistically, lowering TOR activity triggers a metabolic shift from fermentation towards efficient respiration and induces stress defenses (similar to worm mTOR inhibition inducing autophagy and stress responses)​pmc.ncbi.nlm.nih.gov. In fact, rapamycin (an mTOR inhibitor) was first shown in yeast to extend lifespan, a finding later replicated in worms, flies, and even mice​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. This underscores the conserved nature of TOR in aging.
• Ras/AC/PKA Pathway: Yeast cells feeding on glucose activate the Ras pathway, which increases cyclic AMP (cAMP) production via adenylate cyclase, thereby activating Protein Kinase A (PKA)​pmc.ncbi.nlm.nih.gov. PKA promotes growth, glycolysis, and inhibits stress response factors. High PKA activity (high glucose conditions) shortens chronological lifespan, while mutations that reduce Ras or PKA signaling (e.g. ras2Δ or lowering glucose levels) extend lifespan​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. This pathway is often considered the yeast analog of an “insulin/IGF-like” nutrient signal, though yeast lack insulin. It responds to carbon source availability. Notably, ras2 mutant yeast (with low PKA activity) are long-lived in stationary phase, similar to how daf-2 mutants are long-lived in worms, both due to entering a stress-resistant state.

Both TOR/Sch9 and Ras/PKA pathways converge on a central integrator kinase called Rim15 in yeast. Rim15, when released from TOR/PKA inhibition, activates downstream transcription factors Msn2/4 and Gis1 pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Msn2 and Msn4 regulate genes with STRE (stress response) elements, and Gis1 regulates genes with PDS elements, together inducing a broad stress resistance and starvation response program​ pmc.ncbi.nlm.nih.gov. This leads to increased antioxidant enzymes (like Mn-SOD, catalases), heat shock proteins (HSPs), metabolic adjustments (e.g., use of alternative carbon sources), and autophagy – all promoting cell survival in quiescence​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Caloric restriction (CR) in yeast (e.g., growing on lower glucose) works largely by downregulating the Ras/PKA and TOR/Sch9 pathways, thereby activating Rim15 and stress responses​ pmc.ncbi.nlm.nih.gov. The outcome is analogous to DR in worms: a shift to maintenance mode. Indeed, interventions such as glucose restriction, mutations in TOR/Sch9, or activation of stress responses in yeast not only extend CLS but also have parallels in extending worm lifespan​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov.

In replicative aging (dividing mother cells), nutrient signaling also matters. Mothers on calorie-restricted medium or with reduced Sch9 activity show slower aging (more divisions). A noteworthy aspect is that respiration (mitochondrial function) becomes important: growing yeast on a non-fermentable carbon source (forcing respiration) can extend replicative lifespan, aligning with the idea that balanced metabolic activity and avoidance of nutrient excess promote longevity​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov.

In summary, yeast aging is strongly modulated by nutrient-sensing pathways: low TOR/Sch9 and low PKA activity (as occur under calorie restriction or certain mutations) lead to life extension by enhancing stress defenses and maintenance​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. This is conceptually very similar to C. elegans, where reduced IIS/mTOR or increased AMPK (nutrient-stress signals) extend lifespan via FOXO, autophagy, etc. The conservation suggests an ancestral eukaryotic mechanism linking nutrient status to longevity.

Sirtuins and Genomic Stability

One of the first longevity genes identified in yeast was SIR2, encoding a NAD⁺-dependent histone deacetylase. SIR2 gained fame when its overexpression was shown to extend yeast replicative lifespan​ pmc.ncbi.nlm.nih.gov. Sir2 helps silence transcription at the ribosomal DNA (rDNA) repeats and telomeres. In aging mother cells, repetitive rDNA sequences can recombine to form extrachromosomal rDNA circles (ERCs), which accumulate in the mother and contribute to senescence​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Sir2 suppresses ERC formation by stabilizing rDNA, thereby delaying the onset of replicative senescence​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. If SIR2 is deleted, yeast mothers have a much shorter RLS, largely because they accumulate toxic ERCs more quickly​ pmc.ncbi.nlm.nih.gov. Deletion of FOB1 (a gene required for replication fork blocking at rDNA) can prevent ERC accumulation and indeed rescues the short lifespan of sir2Δ cells​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. This established that genome stability, particularly at rDNA, is a key determinant of yeast longevity. It’s a unique aging mechanism in yeast: ERC accumulation has no analog in multicellular somatic aging, but it is conceptually similar to genomic instability contributing to aging.

Sir2’s effects go beyond rDNA: it also helps retain damaged proteins in the mother cell during division (so that daughters are born rejuvenated). In sir2Δ mutants, damaged oxidized proteins are less efficiently sequestered in the mother, causing daughters to inherit more damage and age faster​ pmc.ncbi.nlm.nih.gov. Thus, Sir2 ensures asymmetric cell division – a youthful reset for progeny – which is crucial for the lineage’s longevity. Sir2 levels decline in old yeast cells, which might reduce silencing and stress defense gene regulation with age​ pmc.ncbi.nlm.nih.gov. This may explain why boosting Sir2 can extend lifespan, as it maintains a more “youthful” gene expression profile longer​ pmc.ncbi.nlm.nih.gov.

The role of sirtuins is conserved: C. elegans sir-2.1 and Drosophila Sir2 overexpression can extend lifespan as well​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. However, in worms and flies the effect of sirtuin on aging can depend on genetic background and context. Nonetheless, the link between NAD⁺-dependent deacetylation, energy metabolism, and aging rate appears in many organisms. Sirtuins likely connect metabolic state to chromatin and gene expression states that favor longevity (for example, by activating stress resistance programs or repressing growth genes).

Beyond Sir2, yeast has other chromatin modifiers affecting aging. For instance, histone proteins themselves: increasing histone gene copy number (to improve chromatin packing) extends RLS, presumably by reducing transcriptional noise and genomic instability with age​ pmc.ncbi.nlm.nih.gov. Conversely, mutations that disrupt chromatin silencing can accelerate aging. These observations in yeast parallel findings in worms that chromatin state (like H3K4 methylation levels) can regulate longevity​ frontiersin.org. It points to epigenetic aging as a cross-species phenomenon: changes in chromatin during aging may be causal, and stabilizing the epigenome can extend lifespan.

Stress Resistance and Proteostasis in Yeast

Just as in worms, enhanced stress resistance is a feature of long-lived yeast. In yeast, the transcription factors Msn2/4 (general stress response regulators) and Gis1 (stationary phase regulator) are pivotal for lifespan extension under calorie restriction or TOR/PKA inhibition​ pmc.ncbi.nlm.nih.gov. These factors drive the expression of genes for antioxidant enzymes (e.g., SOD2 for superoxide dismutase, CTA1 for catalase), heat shock proteins, DNA damage repair enzymes, and metabolic adaptors. As a result, yeast cells with active Msn2/4 and Gis1 are better at handling heat, oxidative stress, and other insults, enabling them to live longer in stationary phase​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. If Msn2/4 or Gis1 are deleted, many longevity interventions (like CR or sch9Δ) fail to extend CLS, indicating these stress responses are required for life extension. This is analogous to worm longevity requiring DAF-16/HSF-1/SKN-1 to induce stress resilience genes.

Autophagy is another conserved longevity mechanism present in yeast. Under nutrient deprivation or low TOR signaling, yeast ramp up autophagy, which is crucial for recycling nutrients and clearing damaged cellular components during aging. Mutations that block autophagy (Atg gene deletions) shorten CLS, especially under calorie restriction, implying that autophagy is a major lifespan-extending process downstream of TOR in yeast​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Similarly, mitophagy (selective autophagy of mitochondria) helps remove dysfunctional mitochondria; its induction via mild mitochondrial uncoupling can extend lifespan in yeast, as seen in worms​ frontiersin.org​ pmc.ncbi.nlm.nih.gov.

The proteasome system also affects yeast aging. Studies identified proteasome regulators like Rpn4 (a transcription factor that upregulates proteasome genes) and Ubr2 (an E3 ubiquitin ligase) as modifiers of lifespan​ pmc.ncbi.nlm.nih.gov. For example, deleting UBR2 or overexpressing RPN4 increases proteasome capacity and extends replicative lifespan by enhancing the clearance of damaged proteins pmc.ncbi.nlm.nih.gov. This mirrors the idea in worms that boosting proteostasis (either via chaperones, autophagy, or proteasome) delays aging.

Mitochondrial ROS play a nuanced role in yeast aging. In chronologically aging yeast, a transient increase in ROS during the growth phase (when TOR/Sch9 is low) can act as a signal to bolster defenses, resulting in lower oxidative damage later in stationary phase​ pmc.ncbi.nlm.nih.gov. This controlled ROS signaling is similar to the mitohormesis concept noted in worms. Long-lived yeast mutants (sch9Δ, ras2Δ) often exhibit an adaptive increase in respiration and ROS early, which triggers antioxidant defenses and leads to overall less ROS accumulation during aging, thus extending lifespan​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Conversely, mutants that cannot mount a proper oxidative stress response or that overproduce ROS will age faster.

In summary, yeast longevity is promoted by a shift from a growth program to a stress-resistant program, just like in worms. Enhanced stress resistance (via Msn2/4, Gis1), robust proteostasis (via chaperones, proteasome, autophagy), and controlled metabolic output (via efficient respiration and mild hormetic ROS) are signatures of yeast cells that age slowly​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. These parallels between yeast and worm underscore the conservation of the cellular biology of aging.

Unique Aspects of Yeast Aging

Despite the similarities, yeast’s unicellular nature means there are aspects of aging that differ from multicellular organisms:

• Replicative Senescence: Yeast mother cells eventually stop dividing after ~20–30 divisions, a phenomenon akin to cellular senescence. The causes include ERC accumulation and other damage that cannot be asymmetrically passed off to daughters​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. In multicellular organisms like worms, most somatic cells are not continuously dividing, so this type of replicative limit is not a factor (worm somatic cells do not undergo Hayflick-style senescence)​frontiersin.org. Instead, replicative senescence in yeast is often compared to the aging of mammalian stem cells or dividing cells, and it provides a model for how cells count divisions and decide to stop.
• Chronological Aging and Cell Death: Chronologically old yeast in culture eventually lose viability, partly due to factors like acidification of the medium (from secreted acetic acid) and oxidative damage. Multicellular animals do not have an exact analog of chronological lifespan, but it can be likened to aging of quiescent cell populations (like neurons or muscle cells that mostly don’t divide). Yeast chronological aging has revealed the importance of nutrient signaling in long-term cell survival, which is relevant to how nutrient deprivation (fasting) can preserve cells in animals​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov.
• No Tissue or Endocrine Interactions: Each yeast cell must autonomously manage its aging. There is no concept of tissue-specific aging or hormone signals between cells affecting aging (though in a population, signaling like quorum sensing or sharing of public goods can play a role in CLS). In contrast, C. elegans aging is an emergent property of an entire organism – for example, neurons in C. elegans produce insulin-like peptides that influence the whole body’s aging via IIS​frontiersin.org​frontiersin.org. Yeast lacks such systemic regulation, which simplifies the analysis but also means certain aging aspects (like the cost of reproduction or inter-tissue communication) are absent.
• Telomere dynamics: Yeast have relatively short telomeres, but thanks to telomerase, telomere shortening is not typically a limiting factor for yeast RLS. In worms (and many multicellular eukaryotes), somatic cells do not use telomerase, but since worm somatic cells don’t divide in adulthood, telomere length is largely maintained across generations via the germline. Thus, telomere attrition is not a cause of aging in C. elegans either (unlike human somatic aging). Both systems instead emphasize other genomic elements (rDNA in yeast, perhaps repetitive elements or mitochondrial DNA in worms) in aging.
• Resetting of Aging: Yeast can undergo a form of rejuvenation when forming spores. If starved, a yeast cell can sporulate, and the resulting spores have their aging “clock” reset to zero upon germination. This is analogous to how a worm’s germline is effectively ageless (each new generation starts fresh). These illustrate how biology has mechanisms to restart life without the age baggage, aligning with the idea that only the germline is immortal in multicellular organisms, whereas the soma ages.

Comparative Analysis: C. elegans vs S. cerevisiae Aging Mechanisms

Despite one being a microscopic worm and the other a single-celled fungus, C. elegans and yeast share strikingly similar aging mechanisms at the molecular level. This is a testament to the deep evolutionary conservation of lifespan regulation. At the same time, differences between them highlight the additional layers of complexity that multicellularity and higher organization introduce into aging.

Similarities in Genetic and Molecular Pathways:

• Nutrient-Sensing and Growth Signaling: Both organisms use nutrient-sensing pathways to modulate aging. In C. elegans, low insulin/IGF-1 and mTOR signaling extends lifespan​frontiersin.org​frontiersin.org. In yeast, low PKA and TOR signaling (e.g., under calorie restriction) extends lifespan​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. In essence, insulin/IGF and TOR pathways in worms correspond to the Ras/PKA and TOR pathways in yeast – all of which promote growth and reproduction when nutrients are abundant, but when downregulated, trigger a shift toward maintenance and stress resistance that prolongs life. The fact that dietary restriction extends lifespan in both yeast and worms through these pathways is a key similarity​pmc.ncbi.nlm.nih.gov​frontiersin.org. It suggests an ancient link between sensing the environment’s richness and deciding an organism’s survival strategy.
• FOXO and Stress Response Transcription Factors: Worm DAF-16 (FOXO) and yeast Msn2/4/Gis1 play analogous roles as transcriptional switches that turn on protective genes under stress or low nutrient signals. When IIS is low, DAF-16 activates antioxidant, detoxification, and repair genes in worms​frontiersin.org. In yeast, when PKA/TOR are low, Msn2/4 and Gis1 induce a similar suite of stress tolerance genes​pmc.ncbi.nlm.nih.gov. Both lead to increased levels of enzymes like superoxide dismutases, heat shock proteins, and other longevity-associated proteins. Likewise, worm SKN-1 (NRF2) has its counterpart in yeast oxidative stress regulators (such as Yap1 or the general stress response via Msn2/4). Thus, improved stress resistance is a shared hallmark of longevity in both systems​frontiersin.org​pmc.ncbi.nlm.nih.gov.
• Proteostasis and Autophagy: Both worms and yeast require robust proteostasis to achieve lifespan extension. Long-lived worms often show upregulation of chaperones (via HSF-1) and increased autophagy (via HLH-30/TFEB), which help clear damaged proteins and organelles​pmc.ncbi.nlm.nih.gov​frontiersin.org. Similarly, long-lived yeast mutants rely on autophagy and efficient protein turnover (proteasome activity) to sustain viability in stationary phase​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. The involvement of autophagy as a conserved longevity mechanism is highlighted by the fact that inhibiting autophagy genes in either organism can block lifespan extension from dietary restriction or TOR pathway mutations​frontiersin.org​pmc.ncbi.nlm.nih.gov. This points to cellular cleanup processes being universally important in aging.
• Sirtuins and Energetic Signaling: The NAD⁺-dependent deacetylase enzymes (sirtuins) influence aging in both yeast and worms. Yeast Sir2 extends lifespan by silencing rDNA and preserving genomic stability​pmc.ncbi.nlm.nih.gov, while worm sir-2.1 interacts with IIS and possibly chromatin to modulate aging​pmc.ncbi.nlm.nih.gov. Both reflect how energy status (NAD⁺ levels) is tied to gene regulation: in low-calorie conditions, high NAD⁺ activates sirtuins, which then promote longevity programs (in yeast by repressing rDNA recombination; in worms by deacetylating targets like DAF-16 or histones). Although the downstream effects differ, the concept of chromatin state influencing longevity is common. Additionally, the AMPK pathway is present in both: yeast SNF1 (AMPK) and worm AAK-2 (AMPK) each help adjust metabolism under low energy and have been implicated in lifespan extension under glucose restriction​frontiersin.org​frontiersin.org.
• Mitochondrial Roles and ROS Signaling: Both organisms show a theme of mitochondrial hormesis – a mild increase in mitochondrial stress or ROS that activates defense mechanisms. In worms, partial ETC disruption extends lifespan by triggering stress responses (UPR^mt, antioxidants)​frontiersin.org. In yeast, a transient mitochondrial ROS signal under CR contributes to longevity by inducing protective responses​pmc.ncbi.nlm.nih.gov. Moreover, efficient mitochondrial metabolism (favoring respiration over fermentation in yeast, or balanced ROS production in worms) correlates with longevity in both​pmc.ncbi.nlm.nih.gov​frontiersin.org. This indicates a conserved sensing of mitochondrial health in the aging process.

Given these parallels, it’s not surprising that many longevity interventions work across species: for example, rapamycin (an mTOR inhibitor) extends lifespan in yeast, worms, flies, and mice​ pmc.ncbi.nlm.nih.gov; caloric restriction does as well​ pmc.ncbi.nlm.nih.gov​ frontiersin.org. The conservation provides evolutionary insight: the core cellular processes that limit lifespan (such as protein damage, energy metabolism, stress response) were present in the last common unicellular ancestors. As evolution proceeded, these processes were repurposed and integrated into more complex regulatory networks in multicellular organisms, but they retained the same basic outcomes. Thus, studies in yeast and worms often echo each other and build a consistent picture of aging as a genetically regulated, environmentally modulated process​ pmc.ncbi.nlm.nih.gov.

Differences Unique to Multicellular Aging:

• Cell-Nonautonomous Regulation: In C. elegans, different tissues communicate to regulate aging. For instance, insulin-like peptides are secreted by neurons and interact with the DAF-2 receptor on distant cells​frontiersin.org. The germline sends signals that affect lifespan of the soma​frontiersin.org. Such endocrine and paracrine regulation has no equivalent in single-celled yeast. Each yeast cell must sense and respond to its environment on its own. This means aging in yeast is purely cell-autonomous, whereas in worms, one tissue’s state (e.g., reproductive status, neuronal signaling) can accelerate or slow aging in other tissues. This complexity in worms allows phenomena like “trade-offs” between reproduction and longevity (e.g., germline removal extends lifespan) which yeast cannot exhibit​frontiersin.org​frontiersin.org.
• Developmental and Reproductive Pathways: C. elegans aging is intertwined with its development. The IIS pathway’s role in dauer formation is a prime example – a developmental decision that also affects longevity​frontiersin.org. The existence of a dauer stage (a non-aging, long-lived larval form) shows how evolution linked environmental conditions to developmental fates and aging. Yeast, by contrast, have simpler developmental switches (like sporulation), and while those can reset aging, they are not the same as an organism altering its life history trajectory. Additionally, worms are semelparous (in laboratory conditions, adults generally reproduce in one period then cease), and recent studies liken worm aging to a “reproductive death” phenomenon where resources expended in reproduction drive post-reproductive aging pathology​frontiersin.org​frontiersin.org. Yeast do not have a concept of a post-reproductive lifespan – as long as a mother can bud, she will, until she senesces. These differences highlight that aging in a multicellular context involves trade-offs (growth vs maintenance, reproduction vs longevity) governed by hormonal and developmental signals, adding layers of regulation absent in yeast.
• Cellular Senescence vs. Organismal Aging: Yeast replicative aging is often used as a model for cellular senescence (e.g., how many divisions can a cell undergo). In multicellular organisms, aging is more about the gradual loss of function in cells that often are no longer dividing. Worm somatic cells do not proliferate in adulthood, so they don’t undergo replicative senescence​frontiersin.org. Instead, worm aging involves things like neurons losing function, muscles degenerating, and intestinal cells accumulating waste (pigments, damaged proteins). Yeast, being single-celled, will either keep dividing or die; they don’t have specialized cells to lose function one by one. Thus, some hallmarks of mammalian aging like senescent cell accumulation or stem cell exhaustion are not present in worms, and certainly not in yeast​frontiersin.org​frontiersin.org. Conversely, yeast-specific aging features like ERC accumulation or mother-daughter asymmetry have no direct parallel in worms. However, both systems do emphasize genomic stability (yeast via rDNA circles, worms via maintaining DNA integrity and epigenetic regulation).
• Tissue Degeneration and Pathology: An aging worm exhibits tissue-specific pathologies – e.g., sarcopenia (muscle wasting), neuronal decline, and sometimes proliferative growths in the uterus due to unfertilized eggs (a pathology in old hermaphrodites)​nature.com​nature.com. These are aspects of aging that arise from multicellularity (e.g., tumorous growths, mechanical damage from reproduction, etc.). Yeast simply die when they can no longer maintain homeostasis; they don’t suffer “symptoms” in the way an organism with organs does. Therefore, the end-of-life phenotype is different: all yeast deaths are essentially cellular level failures, whereas worms (and higher animals) have a period of decline with various dysfunctions in parallel. This makes C. elegans a better model for the systems biology of aging, whereas yeast is a cleaner model for the cell biology of aging.

Despite these differences, studying yeast and worms in tandem has been extraordinarily fruitful. Many longevity genes were first found in one and then discovered to have analogous effects in the other. For example, the age-extending effect of sirtuins was found in yeast and later seen in worms​ pmc.ncbi.nlm.nih.gov. Conversely, insulin/FOXO signaling’s role in aging was found in worms and then aspects of it (the downstream stress responses) were noted in yeast stress resistance and in higher organisms​ frontiersin.org​ pmc.ncbi.nlm.nih.gov. The comparison of yeast and worm aging provides evolutionary insights: it appears that the common ancestor of fungi and animals already had molecular systems to regulate longevity in response to nutrients and stress. Multicellular animals built on these foundations, adding endocrine regulation and dividing labor among tissues, but did not reinvent the core mechanisms. For instance, both yeast and worm longevity are enhanced by limiting protein synthesis (via TOR/S6K or translation factor mutations)​ frontiersin.org​ pmc.ncbi.nlm.nih.gov, indicating conservation of the disposable protein synthesis theory (i.e., diverting resources from growth to maintenance). Similarly, both have longevity gain from upregulating stress responses, supporting the stress theory of aging in a conserved manner.

To summarize the comparison, the table below highlights a few key pathways and how they manifest in C. elegans vs. S. cerevisiae:

Pathway / Factor	Aging in C. elegans (Multicellular)	Aging in S. cerevisiae (Single-celled)
Insulin/IGF-1 Signaling (IIS)	Central longevity pathway: DAF-2 (insulin/IGF receptor) -> AGE-1 (PI3K) -> AKT -> inhibits DAF-16 (FOXO). Low IIS = DAF-16 active = lifespan extended​frontiersin.org​frontiersin.org. Coordinates development (dauer) and aging.	No insulin hormone; nutrient signaling via Ras/PKA and Tor/Sch9 plays an analogous role. High glucose -> Ras/PKA active (shortens lifespan); low nutrients -> low PKA -> activates stress responses for longevity​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov.
mTOR Pathway	let-363 (mTOR) and RSKS-1 (S6K) promote growth and protein synthesis. Inhibition of mTOR (genetically or by rapamycin) extends lifespan, partly via inducing autophagy​frontiersin.org​frontiersin.org. Works in parallel to IIS​frontiersin.org​frontiersin.org.	TOR (TORC1) and S6K (Sch9) drive growth. Decreased TOR/Sch9 signaling (rapamycin, tor1 or sch9 mutants) extends both replicative and chronological lifespan​pmc.ncbi.nlm.nih.gov. Triggers stress response and autophagy, similar to worms​pmc.ncbi.nlm.nih.gov.
AMPK & Energy Sensing	AAK-2 (AMPK) is activated under low energy (AMP↑). Extends lifespan by phosphorylating DAF-16 and other factors, enhancing stress resistance​frontiersin.org​frontiersin.org. Required for dietary restriction benefits​frontiersin.org.	SNF1 (AMPK homolog) activates during glucose depletion, shifting metabolism to alternative carbon sources. Indirectly contributes to longevity under calorie restriction (by helping downregulate PKA and upregulate stress responses)​pmc.ncbi.nlm.nih.gov​frontiersin.org.
Sirtuins (Sir2 family)	sir-2.1 (SIRT1 ortholog) deacetylase can extend lifespan when overexpressed​pmc.ncbi.nlm.nih.gov. Interacts with DAF-16 and likely alters chromatin to promote longevity. Part of low-calorie longevity pathway (NAD⁺-dependent)​frontiersin.org.	SIR2 deacetylase extends replicative lifespan by silencing rDNA and preventing extrachromosomal rDNA circle accumulation​pmc.ncbi.nlm.nih.gov​pmc.ncbi.nlm.nih.gov. sir2Δ shortens lifespan, while extra copies lengthen it​pmc.ncbi.nlm.nih.gov. First shown aging gene; ties metabolism to genome stability.
FOXO & Stress TFs	DAF-16 (FOXO) is master regulator of longevity: induces antioxidant, chaperone, and metabolic genes​frontiersin.org. Works with HSF-1 (heat shock factor) and SKN-1 (NRF2) to enhance proteostasis and detoxification​pmc.ncbi.nlm.nih.gov​frontiersin.org. HSF-1 and SKN-1 are required for full lifespan extension in IIS and DR models.	No FOXO in yeast, but Msn2/4 (stress response factors) and Gis1 (stationary phase factor) serve a similar role​pmc.ncbi.nlm.nih.gov. Under low PKA/TOR, Msn2/4/Gis1 activate genes (SODs, HSPs, etc.) for stress defense​pmc.ncbi.nlm.nih.gov. These are required for yeast longevity under CR or stress​pmc.ncbi.nlm.nih.gov. Yeast Hsf1 mediates heat shock response, important for survival but less studied in aging directly.
Proteostasis (Chaperones, Proteasome, Autophagy)	Strong proteostasis upregulation in longevity: HSF-1 elevates chaperones (e.g., HSP-70)​pmc.ncbi.nlm.nih.gov; autophagy (via TFEB/HLH-30) is induced by low IIS/mTOR and required for lifespan extension​frontiersin.org. Proteasome activity and protein turnover are generally higher in long-lived worms.	Proteostasis is key for long-lived yeast: CR and sch9Δ mutants show increased autophagy and require it for lifespan extension​pmc.ncbi.nlm.nih.gov. Proteasome capacity (regulated by Rpn4) influences replicative lifespan​pmc.ncbi.nlm.nih.gov. Chaperones (HSP104, HSP70) help maintain protein folding in aged cells; overexpression can extend CLS.
Mitochondrial Function	Mild mitochondrial dysfunction (clk-1, isp-1 mutations) extend lifespan by activating UPR^mt and antioxidative stress pathways (mitohormesis)​frontiersin.org. Mitochondrial dynamics and mitophagy contribute to removing damaged mitochondria in aging​frontiersin.org​frontiersin.org.	Respiratory metabolism (mitochondria) prolongs lifespan relative to fermentation. sch9Δ or CR leads to increased mitochondrial respiration and an adaptive ROS signal that ultimately lowers oxidative damage​pmc.ncbi.nlm.nih.gov. Mitochondrial mutations (e.g., cyc1Δ) can extend CLS via hormesis, but severe defects are detrimental.
Reproduction and Aging	Clear trade-off: Germline removal -> lifespan extension via DAF-16 and DAF-12 (hormonal signaling)​frontiersin.org​frontiersin.org. Insulin signaling ties to reproductive status (food plentiful -> reproduce, age faster; food scarce -> dauer, slow aging). Multicellular coordination: signals from reproductive tissues and neurons modulate aging.	Single-cell organism has no separate germline; every division is reproduction. No endocrine reproductive signals. However, nutrient signals (like in mating or sporulation conditions) can affect survival. Yeast can enter quiescence or spores to survive harsh conditions indefinitely, “resetting” aging, whereas worms have a dedicated immortal germline vs mortal soma distinction.
Cellular Senescence	Somatic cells are post-mitotic; no replicative senescence in soma​frontiersin.org. Aging is due to damage accumulation and loss of function in cells/tissues. Apoptosis of cells is minimal in normal aging (worms mostly die from functional decline, not programmed cell death).	Mother cells undergo replicative senescence after ~20–30 divisions, partly due to ERCs and damage accumulation​pmc.ncbi.nlm.nih.gov. This is a form of cellular senescence (cessation of division). Yeast also exhibit markers of cell aging (e.g., enlargement, sterility, surface damage). Chronologically aged cells die from cell death pathways reminiscent of apoptosis or necrosis (acetic acid-induced).

Evolutionary insights: The comparison above illustrates that the fundamental levers of aging are ancient and conserved. Nutrient sensing, energy metabolism, and stress responses were likely part of a primordial survival strategy: in good times, grow and reproduce; in hard times, hunker down and invest in maintenance. Yeast, being single-celled, embody this strategy in each cell’s decision to grow or enter stationary phase. C. elegans and other animals have built on this by evolving hormone signals and developmental checkpoints (like dauer diapause) to coordinate the entire organism’s response to the environment​ frontiersin.org​ frontiersin.org. The result is that many longevity-promoting interventions (genetic or environmental) work in vastly different organisms, underscoring common mechanisms​ pmc.ncbi.nlm.nih.gov. At the same time, the divergence reveals that aging can be influenced by organism-specific factors (e.g., reproductive organs in worms, or unique genomic elements in yeast). Studying both models side-by-side provides a more complete understanding: what we learn in one often guides discoveries in the other. These simple eukaryotes have paved the way for tackling aging in more complex animals, including humans, by highlighting critical pathways like IIS/FOXO, mTOR, AMPK, sirtuins, and proteostasis networks that appear to govern the pace of aging across the tree of life​ frontiersin.org​ pmc.ncbi.nlm.nih.gov.

Conclusion

Aging is a multifaceted process controlled by conserved genetic and molecular mechanisms. Research in C. elegans has revealed that longevity can be dramatically altered by single-gene mutations in nutrient-sensing pathways (e.g., daf-2 insulin receptor)​ frontiersin.org, and that long life is associated with enhanced stress defenses, efficient metabolism, and robust proteostasis. Similarly, yeast aging studies uncovered pathways like TOR and Sir2 that regulate lifespan by balancing growth and maintenance​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. Comparing the two models highlights a core theme: when an organism (or cell) devotes resources to stress protection and metabolic economy (often enforced by low nutrient signaling), aging slows down; when resources go to rapid growth and reproduction (high nutrient signaling), aging accelerates. The differences between yeast and worms remind us that in a multicellular context, additional factors (developmental programs, cell-to-cell signals) modulate this balance.

In essence, C. elegans provides a view of how an entire organism ages, integrating signals from various tissues, while S. cerevisiae provides a cell-centric view of aging. Together, they have led to a cohesive understanding of eukaryotic aging mechanisms. These insights are now being applied to higher organisms: for example, findings in worms and yeast prompted studies showing that reducing IGF-1 or mTOR signaling extends lifespan in mice​ pmc.ncbi.nlm.nih.gov​ pmc.ncbi.nlm.nih.gov. The evolutionary conservation gives hope that by targeting these key pathways, we might improve healthspan and treat age-associated diseases in humans. As we continue to untangle aging’s complexities, simple model organisms will remain invaluable guides to the foundational mechanisms that time our lives.

Sources: The information in this report is drawn from research literature on C. elegans and yeast aging, including reviews and primary studies that identified the IIS/FOXO pathway​

frontiersin.org​

frontiersin.org, dietary restriction mechanisms​

frontiersin.org​

pmc.ncbi.nlm.nih.gov, stress response factors​

pmc.ncbi.nlm.nih.gov​

pmc.ncbi.nlm.nih.gov, mitochondrial effects​

frontiersin.org​

pmc.ncbi.nlm.nih.gov, and genomic stability elements​

pmc.ncbi.nlm.nih.gov, among others.

These models collectively highlight the genetic pathways and molecular processes that influence longevity across species.