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c-myc

Properties1
aliasesMYC, c-Myc, Myc, MYCC, bHLHe39

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c-MYC (MYC)

The fourth Yamanaka factor — a master transcriptional amplifier that drives cell growth, proliferation, and ribosome biogenesis. In the context of aging, c-MYC is a double-edged proto-oncogene: its activity promotes cancer risk and oncogene-induced senescence (OIS), yet its partial reduction in mice extends lifespan by ~15% with broad healthspan benefits. In partial reprogramming, c-MYC is the “M” of the original OSKM cocktail but is deliberately omitted in safer OSK-only protocols (Sinclair group and others) due to its oncogenic and teratoma-inducing potential.

Identity

  • UniProt: P01106 (MYC_HUMAN) — manually reviewed (Swiss-Prot)
  • NCBI Gene: 4609
  • HGNC symbol: MYC (official symbol); aliases MYCC, bHLHe39
  • Ensembl: ENSG00000136997
  • Mouse ortholog: Myc (one-to-one ortholog; highly conserved)
  • GenAge ID: 39 (evidence from both human cell systems and model organisms)
  • Chromosomal location: 8q24.21 — the locus involved in Burkitt lymphoma translocations
  • Length: 454 amino acids; ~50.6 kDa

Protein class and structure

c-MYC is a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor. It is structurally and functionally incomplete as a monomer: it must heterodimerize with its obligate partner max to bind DNA at E-box sequences.

Key structural domains

DomainResidues (approx.)Function
N-terminal transactivation domain (TAD)1–143Recruits co-activators (CBP/p300, TRRAP/GCN5); contains 9aaTAD motif (~115–123)
MYC box I (MBI)~45–63Phosphorylation-dependent stability regulation; Thr-73 and Ser-77 sites; FBXW7 degron
MYC box II (MBII)~128–143Core transactivation; essential for oncogenic transformation
Basic region~370–379DNA recognition; contacts E-box bases; UBR5-degron overlap
Helix-loop-helix (HLH)~383–421Dimerization interface with MAX
Leucine zipper (LZ)~428–449Stabilizes MYC-MAX heterodimer

Dimerization partner MAX

c-MYC is inactive without max. The MYC-MAX heterodimer binds canonical E-box sequences (core: 5’-CACGTG-3’) and activates transcription. Importantly, MAX also dimerizes with the MAD/MNT family of repressors, which compete with MYC for E-box sites and repress MYC target genes — making the MYC:MAD/MNT ratio a key determinant of net transcriptional output in proliferating vs quiescent cells. unsourced — MYC:MAX:MAD competitive binding quantitation in aging tissues not documented; stub for mad-max-network.

Function

c-MYC is a global transcriptional amplifier — not a classical sequence-specific activator of a small gene set, but a broad enhancer of already-active genes 1. A promoter-array study found that ~15% of human gene promoters are broadly bound by Myc; downstream of this, an estimated 15–20% of all genes are directly regulated by MYC 1. This makes it one of the most far-reaching transcriptional regulators in the cell.

Core functions

  • Cell growth and mass accumulation — activates ribosomal protein genes, rDNA transcription (via RNA Pol I), and tRNA synthesis to drive biomass production
  • Cell cycle entry and progression — activates E2F targets (CDC25A, CDK4, cyclin D2/E); represses p21/CDKN1A and p27/CDKN1B to release CDK brakes
  • Ribosome biogenesis — among the strongest inducers of ribosomal RNA and ribosomal protein transcription; coordinates RNA Pol I, II, and III
  • Metabolic reprogramming — promotes aerobic glycolysis (Warburg effect) and glutamine utilization; activates LDHA, PDK1, and glutaminase (GLS)
  • Stem cell maintenance — one of the four Yamanaka factors; promotes pluripotency gene programs; required for rapid early embryonic proliferation

Regulation of c-MYC protein stability

c-MYC has a strikingly short protein half-life of approximately 15–20 minutes in most cell types 1. Two sequential phosphorylation events on the N-terminal degron govern stability:

  1. Ser-62 phosphorylation by ERK or CDK2 initially stabilizes MYC
  2. Thr-73 phosphorylation (or the adjacent Ser-77) by GSK3β or DYRK2 (primed by Ser-62 phosphorylation) recruits SCF(FBXW7), the principal E3 ubiquitin ligase targeting MYC for proteasomal degradation

The deubiquitinases usp28 (in the nucleoplasm) and USP36 (in the nucleolus) counteract FBXW7, providing spatial regulation of MYC stability. Loss-of-function mutations in FBXW7 are among the most common in human cancers, contributing to MYC hyperactivation via protein stabilization.

Role in partial reprogramming

Original OSKM cocktail

In 2006, Takahashi and Yamanaka demonstrated that co-expression of four transcription factors — OCT4, SOX2, KLF4, and c-MYC (OSKM) — in mouse fibroblasts generates induced pluripotent stem cells (iPSCs) 2. c-MYC’s role in this cocktail is primarily to:

  1. Open chromatin globally, making target loci accessible for OCT4/SOX2/KLF4
  2. Activate the proliferation machinery required for the rapid cell divisions during reprogramming
  3. Suppress differentiation-associated gene programs

The inclusion of c-MYC dramatically improved reprogramming efficiency. The 2006 paper noted that “use of c-Myc may not be suitable for clinical applications” and demonstrated that subcutaneous injection of iPS cells into nude mice produced teratomas containing tissues of all three germ layers — a standard pluripotency demonstration that simultaneously highlighted the tumorigenic potential of cells retaining active reprogramming transgenes 2. The specific finding that chimeric mice developed tumors due to c-MYC reactivation was reported in a follow-up study (Okita et al. 2007, Nature 448:313–7) not verified here. needs-replication

OSK protocols: deliberate omission of c-MYC

The Sinclair laboratory and other groups pursuing partial reprogramming for aging reversal use OSK (OCT4, SOX2, KLF4) without c-MYC 3. The rationale:

FactorOSK (Sinclair/aging protocols)OSKM (Ocampo 2016; original iPSC)
Reprogramming efficiencyLowerHigher
Teratoma riskReducedPresent (if c-Myc reactivated)
Oncogenic riskLowerHigher
Clinical translatabilityMore favorableUnfavorable
Epigenetic age reversalDemonstrated (Lu 2020, Yang 2023)Demonstrated (Ocampo 2016)

The tradeoff is real: omitting c-MYC requires longer, more controlled TF expression to achieve comparable epigenetic remodeling, and the molecular mechanism does not depend on c-MYC’s proliferative function — it depends on OCT4/SOX2/KLF4’s chromatin-remodeling and TET demethylase recruitment activity. See partial-reprogramming (verified) for full experimental detail.

needs-replication — Whether OSK without c-MYC achieves equivalent epigenetic rejuvenation to full OSKM in all tissue contexts has not been systematically tested across tissue types.

Aging relevance

Oncogene-induced senescence (OIS)

Paradoxically, acute oncogene activation (including MYC overexpression above a threshold) triggers a cellular senescence program rather than unlimited proliferation — a tumor-suppressive response called oncogene-induced senescence (OIS). The key mechanism for Myc-induced OIS involves p19ARF (mouse) / p14ARF (human):

  1. Sustained MYC activation induces Cdkn2a locus transcription → p19ARF / p14ARF protein accumulation
  2. ARF sequesters MDM2, stabilizing p53
  3. p53 transcriptionally activates p21/CDKN1A → cell cycle arrest → senescence

Myc also drives apoptosis under limiting survival signals, creating a “proliferate-or-die” switch: MYC overexpression combined with serum/growth factor deprivation in primary mouse embryo fibroblasts (MEFs) triggers rapid apoptosis rather than senescence 4. This apoptosis response is significantly attenuated by ARF loss or p53 loss — ARF-null and p53-null MEFs show markedly reduced apoptosis compared to wild-type MEFs under the same conditions (Figure 4 and 5A, Zindy 1998). The requirement for cytochrome c release via the intrinsic mitochondrial pathway is not established by Zindy 1998 — that mechanistic link comes from other literature. unsourced — intrinsic apoptosis pathway downstream of MYC/ARF/p53 needs a separate citation.

DimensionStatus
Pathway conserved in humans?yes (p14ARF is the human ortholog of mouse p19ARF; same MDM2-p53 axis)
Phenotype conserved in humans?yes (MYC amplification drives human cancer; ARF loss accelerates tumorigenesis)
Replicated in humans?yes (epidemiology of Burkitt lymphoma and MYC amplification in human cancers)

Myc haploinsufficiency and longevity in mice (Hofmann 2015)

The most direct aging-relevant finding: Myc heterozygous (Myc+/-) mice live longer than wild-type littermates with broad improvements in healthspan 5. Key findings from this study:

  • Extended median lifespan: 20.9% increase in females (Myc+/+ N=37, Myc+/- N=37; p<0.001, log-rank) and 10.7% increase in males (Myc+/+ N=42, Myc+/- N=42; p<0.001, log-rank); 15.1% combined for both sexes (Figure 1B). Strain: C57BL/6 (backcrossed ≥10 generations). Maximum lifespans were commensurately extended.
  • Reduced age-related pathology: less cardiac fibrosis (p=0.047, Masson’s trichrome, n=11–14), preserved bone density / less osteoporosis in females (p=0.021/0.045 micro-CT, n=3–7), and improved immunosenescence (CD4/CD8 ratio, naive/memory T-cell ratios maintained; p<0.05)
  • Improved metabolic health: decreased serum free IGF-1 (ELISA; p=0.049 young, p=0.034 old, n=5–12); elevated AMPK phosphorylation (pAMPK/AMPK ratio, p=0.039); reduced pAKT/AKT (p=0.032/0.047) and pS6K/S6K (p=0.048/0.043) in liver and muscle
  • Reduced protein translation rate: in vivo 3H-phenylalanine incorporation assay, p=0.044 (n=5, 5–7 months males)
  • Transcriptomic analysis (liver, muscle, adipose; Affymetrix arrays) revealed enrichment in metabolic and immune process signatures; partial overlap with caloric restriction and metformin transcriptomes but not a simple phenocopy
  • Important caveat: Myc+/- mice do not show improvements in stress management pathways (ROS, DNA damage foci, genotoxic stress markers, p21/p16 induction, cellular senescence rates) compared to Myc+/+ — a key contrast with several other longevity models. The lifespan extension is attributed primarily to reduced ribosome biogenesis/translation and improved metabolic signaling, not to stress resistance.

This mechanistically connects c-MYC to the mtor / ampk / insulin-igf1 longevity axis: reducing MYC expression phenocopies several aspects of mTOR inhibition or dietary restriction, though the authors note TOR activity changes are likely downstream of the higher metabolic rate in Myc+/- mice, and AMPK activation is probably secondary rather than a direct MYC→AMPK effect. needs-human-replication

DimensionStatus
Pathway conserved in humans?yes (MYC-driven translation and mTOR crosstalk conserved)
Phenotype conserved in humans?unknown (no human equivalent of Myc haploinsufficiency studied prospectively)
Replicated in humans?no — mouse-only; no independent replication as of 2026-05-05

needs-replication — Hofmann 2015 is currently the primary paper demonstrating longevity from Myc haploinsufficiency; independent mouse replication has not been reported as of 2026-05-05.

MYC in Drosophila aging

GenAge (entry 39) records that MYC overexpression in Drosophila somatic cells increases somatic mutation frequency and reduces median and maximum lifespan by up to 47%; conversely, haploinsufficiency extends fly lifespan by approximately 14% 6. The fly and mouse findings converge: dosage reduction of Myc consistently extends lifespan across species. needs-human-replication

Disease associations

Burkitt lymphoma — the canonical Myc translocation

Burkitt lymphoma is defined by a chromosomal translocation placing the MYC gene at 8q24 under the control of immunoglobulin locus enhancers 7:

  • t(8;14) — MYC placed under control of the immunoglobulin heavy chain (IgH) enhancer (~80% of Burkitt cases)
  • t(2;8) — MYC placed near IgÎş light chain locus
  • t(8;22) — MYC placed near Igλ light chain locus

In all cases, constitutive, high-level MYC expression in B cells drives aggressive lymphoma. This is among the most clinically and molecularly characterized examples of oncogene activation by regulatory element capture.

MYC amplification in other cancers

MYC amplification (gene copy number gain) or protein overexpression is found in a broad range of solid tumors including breast (~20%), colorectal, non-small cell lung, and hepatocellular carcinomas. MYCN (N-Myc) amplification is a defining feature of neuroblastoma; MYCL (L-Myc) is amplified in small-cell lung cancer. The MYC family thus represents the most broadly implicated oncogene family in human cancer.

Double-hit and triple-hit lymphoma

High-grade B-cell lymphomas with concurrent MYC and BCL2 rearrangements (double-hit) or MYC, BCL2, and BCL6 rearrangements (triple-hit) carry poor prognosis and are directly relevant to senolytic targeting: BCL2 overexpression protects MYC-driven lymphoma cells from apoptosis, a dependency that BCL2 inhibitors (venetoclax) exploit. This intersects with the bcl-2-family pathways relevant to cellular-senescence and apoptotic escape.

Regulation

Transcriptional

  • MYC mRNA is very short-lived (~30 min); the gene is highly responsive to mitogenic signaling (growth factors, Wnt, Notch, Hedgehog)
  • Regulated at multiple levels: promoter activity, RNA Pol II elongation (BRD4-dependent), mRNA stability (AUF1, HuR), and translation
  • BET bromodomain inhibitors (JQ1, I-BET762) suppress MYC transcription by displacing BRD4 from the MYC super-enhancer — a therapeutic approach in MYC-driven cancers

Post-translational (protein stability)

See “Regulation of c-MYC protein stability” above. The phospho-degron (Thr-73/Ser-77 → SCF(FBXW7)) is the primary stability control. In many cancers, FBXW7 is mutated, FBXW7 protein is lost, or MYC degron residues are mutated — all leading to MYC stabilization.

MAX availability

Reduction of MAX protein forces a redistribution of remaining MYC into potentially active or inactive complexes depending on context; MAX heterozygous mice show similar longevity effects to Myc heterozygous mice in at least one study unsourced.

Cross-references

EntityRelationship
partial-reprogramming (verified)OSKM cocktail includes c-MYC; OSK protocols omit it due to oncogenic risk; central tension documented there
information-theory-of-aging (verified)Partial reprogramming context; c-MYC role in original OSKM vs. safer OSK approach
max (stub)Obligate heterodimerization partner; MYC is inactive without MAX
fbxw7 (stub)Primary E3 ubiquitin ligase; loss of FBXW7 stabilizes MYC in many cancers
p19-arf (stub)ARF/p14ARF mediates MYC-induced oncogene-induced senescence via MDM2-p53
p53 (verified)Downstream of ARF → MDM2 relief; p53 executes senescence or apoptosis after MYC overactivation
cellular-senescenceMYC is a key OIS inducer; MYC dosage reduction may reduce senescent cell burden (mechanism unclear)
mtor (verified)Myc+/- mice show reduced mTOR/AKT/S6K signaling; mechanistic overlap with mTOR longevity axis
ampk (verified)Myc+/- mice show elevated AMPK activity; potential mechanistic link to AMPK longevity effects
insulin-igf1 (stub)Myc+/- mice show decreased serum IGF-1; connects MYC dosage to the IGF-1 longevity axis
oct4 (planned stub)Core OSK reprogramming factor co-expressed with c-MYC in OSKM
sox2 (planned stub)Core OSK reprogramming factor
klf4 (planned stub)Core OSK reprogramming factor
bcl-2-family (stub)MYC-driven lymphomas frequently co-amplify BCL2; senolytic context

Limitations and gaps

needs-human-replication — The Myc+/- longevity finding (Hofmann 2015) is mouse-only; no prospective human equivalent exists; haploinsufficiency of MYC in humans is not a documented heritable condition with longevity data.

needs-replication — Hofmann 2015 is a single study; independent replication of the lifespan extension (20.9% females, 10.7% males, 15.1% combined) in Myc+/- C57BL/6 mice has not been reported as of 2026-05-05.

needs-human-replication — Drosophila Myc haploinsufficiency lifespan extension (GenAge entry 39) is from a different phylum; mechanistic conservation with mammalian aging is plausible but not directly tested.

dose-response-unclear — The dose-response between c-MYC expression level and the oncogenic vs. longevity-promoting outcome is poorly characterized in normal somatic tissues. Partial reduction (haploinsufficiency) extends lifespan; excessive reduction would impair tissue maintenance. The optimal MYC dosage for longevity vs. cancer prevention is not established.

no-mechanism — The mechanism by which reduced MYC expression extends lifespan in mice is not fully resolved. The Hofmann 2015 paper links it to reduced protein translation and mTOR/IGF-1 axis downregulation, but causal assignments within the mechanistic chain remain incomplete.

unsourced — Whether the oncogene-induced senescence mechanism downstream of MYC amplification quantitatively contributes to the SASP burden and inflammaging in normally aged (non-cancerous) tissues has not been directly measured; this remains a plausible but undemonstrated connection.

Footnotes

Footnotes

  1. doi:10.1016/j.cell.2012.03.003 · review · model: human and mouse · “MYC on the Path to Cancer” — comprehensive review of MYC as transcriptional amplifier, role in metabolism, and oncogenesis · protein t½ ~15–20 min (citing Gregory and Hann 2000); ~15% of promoters broadly bound by Myc (promoter-array); 15–20% of all genes directly regulated · 3,284 citations; FWCI=73.6 · Cell 149:22–35, Mar 2012 · Dang CV ↩ ↩2 ↩3

  2. doi:10.1016/j.cell.2006.07.024 · in-vitro · model: Mus musculus embryonic fibroblasts (MEFs) and adult tail-tip fibroblasts (TTFs); Fbx15βgeo/βgeo reporter strain on C57BL/6-129 hybrid background · discovery of iPSC induction by OCT3/4+SOX2+KLF4+c-MYC (OSKM); teratomas (all 3 germ layers) from subcutaneous injection into nude mice; clinical inapplicability of c-Myc noted by authors · Cell 126:663–676, Aug 2006 · Takahashi K, Yamanaka S ↩ ↩2

  3. doi:10.1038/s41586-020-2975-4 · in-vivo · model: Mus musculus (optic nerve crush injury model; retinal ganglion cells) · OSK (without c-MYC) AAV delivery restores youthful epigenetic patterns and reverses vision loss · Lu Y, Brommer B, Tian X, et al. · Nature 588:124–129, 2020 · also cited in partial-reprogramming (verified) — footnote defined locally here to avoid cross-page resolution failure ↩

  4. doi:10.1101/gad.12.15.2424 · in-vitro (primary MEFs: wild-type, ARF-/-, p53-/-, p21-null, Rb-null) · model: Mus musculus embryo fibroblasts · retroviral myc overexpression ± serum deprivation · “Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization” · ARF/p53-dependent apoptosis in serum-deprived MEFs confirmed; cytochrome c / mitochondrial pathway not examined in this paper · Genes Dev 12:2424–2433, 1998 · Zindy F, Eischen CM, Randle DH, et al. ↩

  5. doi:10.1016/j.cell.2014.12.016 · in-vivo (Myc+/- haploinsufficient mice) · model: C57BL/6 Mus musculus (backcrossed ≥10 generations) · n=37/37 females; 42/42 males · median lifespan increase 20.9% females, 10.7% males, 15.1% combined (log-rank p<0.001 both sexes) · reduced serum IGF-1, elevated AMPK activity, reduced pAKT and pS6K signaling, reduced translation rate · no improvement in stress-management or senescence pathways · Cell 160:477–488, Jan 2015 · Hofmann JW, Zhao X, De Cecco M, et al. ↩

  6. GenAge entry 39 (MYC) — https://genomics.senescence.info/genes/entry.php?hgnc=MYC — model: Drosophila melanogaster (Myc overexpression increases somatic mutation frequency, reduces median/max lifespan by up to 47%; haploinsufficiency extends lifespan by ~14%); also notes WRN and TERT protein interactions. Accessed 2026-05-05. ↩

  7. doi:10.1073/pnas.79.24.7824 · observational (cytogenetics) · model: human Burkitt lymphoma cell lines · “Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells” · 1,760 citations · no-fulltext-access — not open-access; no local PDF in a local paper archive (status: not_oa). Translocation claims (t(8;14)/t(2;8)/t(8;22)) are consistent with all secondary literature but cannot be verified against primary source text. ↩

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