A Comparative Perspective on HDAC2 and PRC2 in Plant and Animal Aging,
Incorporating “Primordial Pathways” and “The Four Horsemen of Aging”
Jeff T Bowles 03/01/2025 [email protected]
Abstract
Recent studies, including Horvath’s landmark universal epigenetic clock (August 2023) and subsequent comparative analyses, highlight four deeply conserved “plant-present” genes—HDAC2, PRC2, SNX1, and LARP1—as key regulators of aging across eukaryotes. Notably, HDAC2 and PRC2 also appear in searches relating to “lamin A”/“progeria,” suggesting that premature aging syndromes may co-opt epigenetic systems first established in plant-like ancestors. SNX1 and LARP1 would also be expected to be found associated with progeria/lamin a but likely not enough studies exist for these genes for studies to appear in this context yet. In parallel, mitochondrial-centered queries underscore genes like c-JUN and HDAC2 as top hits for mammalian mitochondrial aging, reflecting broad conservation with insect aging pathways. Here, we integrate new insights from two recent articles—“Primordial Pathways of Aging” (Feb 2025) and “The Four Horsemen of Aging” (Jan 2025)—to illustrate how these universal genes bridge plant vascular senescence and metazoan aging modules. We argue that progeria (and other accelerated aging syndromes) exploits fundamental chromatin and mitochondrial regulatory circuits with roots in our earliest eukaryotic forebears.
1. Introduction
In his universal epigenetic clock study (Nature, Aug 2023), Steve Horvath identified a set of at least 49 mammalian aging genes (48 plus SP1 (and others) in later revisions) that appear in multiple vertebrates, with some extending into insects, plants, or both. Two related articles, “Primordial Pathways of Aging: The Four Plant-Animal Genes That Shaped Eukaryotic Longevity” (Feb 2025) and “The Four Horsemen of Aging” (Jan 2025), then explored how only four of these 49 genes—LARP1, SNX1, HDAC2, and PRC2—are consistently found in plants, highlighting their deep evolutionary significance.
From a PubMed co-occurrence standpoint, so far only HDAC2 and PRC2 among these four plant-present genes showed hits for “lamin A”/“progeria,” thereby linking them to accelerated-aging phenotypes in humans. It is expected that LARP1 and SNX1 while join this list in the future. Remarkably, analyses of mitochondrial references also position HDAC2 among the top-scoring genes, indicating a role for epigenetic remodeling in mitochondria-rich tissues—an aging axis broadly shared with insects (e.g., c-JUN in Drosophila stress response).
In parallel, Jeff T. Bowles’s “Four Horsemen of Aging” model posits that multiple, independently evolved aging “modules” (vascular/structural, mitochondrial, DNA repair/immune, and sexual reproduction–associated) can be co-opted or sabotaged by factors like “short LARP1,” a nuclear lncRNA. The result is a deep synergy wherein HDAC2 and PRC2 (originally vital for epigenetic and structural regulation in early eukaryotes) remain prime targets for misregulation in advanced aging syndromes.
2. The Four Plant Genes and Their Role in Progeria
2.1 From “Primordial Pathways”:
According to “Primordial Pathways of Aging,” only four of Horvath’s 49 genes—LARP1, SNX1, HDAC2, and PRC2—appear across both plants and animals. Each gene encodes a fundamental regulatory mechanism:
-
LARP1
- RNA-binding protein (or a nuclear lncRNA isoform) that modulates mRNA stability.
- Though top-ranked in Horvath’s clock, LARP1 yielded zero PubMed hits with “lamin A” or “progeria” in our table, likely reflecting the lesser-known “short LARP1” isoform that Bowles proposes is central to aging adn triggers agng by causing the misplicing or suppression of various mRNAs for critical proteins like WRN, ATM, XP/CS, and lamin A.
-
SNX1
- Sorting Nexin 1, crucial in endosomal trafficking and receptor recycling.
- Also shows no co-occurrence with progeria in the query, but is expected to show up in the future; it is essential for cell homeostasis.
-
HDAC2
- Histone deacetylase 2, removing acetyl groups on histones to alter gene expression.
- Displays multiple (“4/2258”) hits for lamin A/progeria, linking it to nuclear envelope integrity and epigenetic aspects of premature vascular/structural aging.
-
PRC2
- Polycomb Repressive Complex 2, methylates histone H3K27 to impose transcriptional silencing.
- Has hits for lamin A/progeria in our PubMed ratio (~3/5660), underlining its relevance to repressive chromatin modifications in rapid aging syndromes.
The fact that HDAC2 and PRC2 co-occur with references to progeria underscores how an accelerated breakdown in nuclear or chromatin architecture may have roots in epigenetic modules common to both plants and animals. In Bowles’s framework, these are “older” systems from a time “when our ancestors were more plant-like,” focusing on vascular-like tissues and basic structural maintenance.
2.2 The “Four Horsemen” View: Progeria as Vestigial Vascular Aging
Bowles’s “Four Horsemen of Aging” model partitions senescence into four sequentially evolved systems:
- System #1 – “Plant-like” structural aging (e.g., lamin A–based deterioration of vascular and connective tissues).
- System #2 – Mitochondrial decline in motile animals.
- System #3 – Advanced DNA repair and immune pathways (e.g., ATM, XP/CS).
- System #4 – Sexual reproduction–linked genomic instability (e.g., WRN, Werner’s syndrome).
Progeria (Hutchinson-Gilford Progeria Syndrome) exemplifies an accelerated version of System #1, involving LMNA mis-splicing and nuclear envelope collapse. Since HDAC2 and PRC2 can modulate chromatin compaction and histone states around the nuclear periphery, they may cooperate—under normal conditions—to regulate the large-scale gene silencing that mature cells require for structural maintenance and differentiation. When misregulated, HDAC2 and PRC2 fail to maintain nuclear architecture, hastening the vascular and connective-tissue deficits characteristic of progeria.
Intriguingly, Bowles’s work suggests that some plant-like vascular aging tasks performed by lamin A in humans may now be vestigial, partially supplanted by Horvath’s broader epigenetic clock. Yet when mutated or mis-spliced, lamin A reverts to a destructive embryonic role (progerin), paralleling how PRC2 or HDAC2—if derailed—can re-initiate “terminal differentiation exit,” echoing plant senescence.
3. Mitochondrial Genes, Insect Comparisons, and Epigenetic Cross-Talk
3.1 The Mitochondrial Table: Top Hits and Their Percentages
A second query examined which of Horvath’s 48 genes appear alongside “mitochondria” in PubMed. The top scorers include:
- c-JUN (3.96%)
- Transferrin (TF) (1.62%)
- ZIC1 (1.60%)
- NANOG (1.20%)
- HDAC2 (1.15%)
The fact that HDAC2 again appears near the top for mitochondrial references reinforces the notion that histone deacetylation intimately affects mitochondrial gene expression, possibly through nuclear-encoded factors that regulate oxidative phosphorylation and ROS management.
3.2 Overlap with Insect Aging Genes
Many of these same “mitochondrial hits”—especially c-JUN—are implicated in insect aging as well. In Drosophila, Jun is crucial for stress responses, neuronal integrity, and lifespan regulation, supporting the notion that epigenetic and transcription-factor networks controlling mitochondrial function arose early in metazoan evolution. Thus, the epigenetic apparatus (in which HDAC2 and PRC2 are major players) is a unifying thread from plants to insects to mammals:
- In insects, c-JUN, NKX2, FOX, T-box genes orchestrate fundamental patterning and stress response.
- In mammals, HDAC2– and PRC2–mediated histone modifications govern both nuclear and mitochondrial aging processes.
- In plants, homologous epigenetic modulators handle organ identity, leaf senescence, and resource reallocation.
4. Short LARP1, Co-option, and the Multi-System Model
Although LARP1 and SNX1 do not show direct hits with lamin A/progeria, the “Four Horsemen of Aging” article emphasizes a possibly unstudied isoform, “short LARP1,” that sabotages transcripts for ATM, XP/CS, WRN, and maybe lamin A. In the presence of defective DNA repair or nuclear envelope factors, HDAC2 and PRC2 can become misregulated, unleashing older aging modules (e.g., vascular collapse akin to progeria). This multi-level synergy may explain how primordial genes like HDAC2 or PRC2—first deployed for basic chromatin sculpting in plants—remain “hijackable” in advanced mammalian progeroid syndromes.
Similarly, mitochondrial decline (System #2) resonates across species: in insects, c-JUN controls stress response to ROS; in mammals, truncated ATM and XP/CS proteins lead to unrestrained mitochondrial damage. The presence of HDAC2 (and sometimes PRC2) among top “mitochondrial hits” underscores a deep functional intersection between nuclear epigenetics and organelle homeostasis, consistent with Bowles’s layered model of evolutionary aging.
5. Evolutionary Perspective and Conclusions
The new comparative genomic data from “Primordial Pathways of Aging” and Bowles’s “Four Horsemen” framework converge on a key insight:
- Plant-Present Genes (HDAC2, PRC2, LARP1, SNX1) lie at the foundation of eukaryotic aging.
- HDAC2 and PRC2 each show direct relevance to lamin A/progeria, suggesting that vestigial “vascular/structural” aging (System #1) persists in modern humans but can become pathologically overactivated (e.g., progeria).
- HDAC2 also emerges among top hits for mitochondrial references, linking epigenetic states to metabolic decline across multiple phyla—including insects.
From an evolutionary standpoint, aging appears not as a mere byproduct of random wear but as a stratified system of epigenetic, mitochondrial, and reproductive-layered modules. Early plant-like ancestors had the seeds of these mechanisms (e.g., HDAC2, PRC2), which then expanded and diversified through insect lineages (e.g., c-JUN, NKX2) and ultimately in vertebrates (WRN, lamin A). Bowles’s concept of short LARP1 as a master “splicing saboteur” further illustrates how these modules can be co-opted to ensure a thorough, multi-system senescence program.
Looking Ahead
- Clinical Implications: Targeting HDAC2 or PRC2 to modulate chromatin plasticity may help slow or reverse aspects of vascular aging, especially in conditions resembling progeria. (LARP1 and SNX1 may alsl be targetable in the future as more data emerges.)
- Evolutionary Geroscience: Understanding how ephemeral or reversible RNA-level “damage” (rather than irreparable DNA damage) drives aging may yield therapies that restore transcript fidelity, with broad translational possibilities in age-related diseases.
- Comparative Approach: Delving deeper into insect and plant models can illuminate how ancient modules (e.g., HDAC2–dependent histone deacetylation) have been repurposed for diverse complexities, from root development to neuronal resilience.
In sum, the interplay among HDAC2, PRC2, and short LARP1 ( and probably SNX1) exemplifies how deeply rooted genes remain pivotal in diseases like progeria and mitochondrial dysfunction. By melding the “Primordial Pathways” and “Four Horsemen” perspectives, we see a coherent evolutionary continuum where epigenetic and mitochondrial regulatory strategies from plant-like ancestors persist into modern mammalian aging—sometimes in tragically accelerated forms like progeria.
Selected References
- Horvath, S. et al. “Universal DNA Methylation Age across Mammalian Tissues.” Nature. 2023.
- Bowles, J.T. “The Four Horsemen of Aging: How 4 Evolved Mammalian Aging Systems Reveal the Missing Half of Evolution.” Online. 1/28/2025.
- Bowles, J.T. “Primordial Pathways of Aging: The Four Plant-Animal Genes That Shaped Eukaryotic Longevity.” Online. 2/27/2025.
- Cao, R. et al. “Role of the Polycomb Group Protein EZH2 (PRC2) in Human Cancer and Aging.” Mol Cell Biol. 2002.
- De Sandre-Giovannoli, A. et al. “Lamin A Truncation in Hutchinson–Gilford Progeria Syndrome.” Science. 2003.
- Wang, Z. et al. “Epigenetic Regulation of Plant Senescence by Histone Deacetylases (HDACs).” Trends Plant Sci. 2020.
lamin A/progeria |
|||||
| ZIC1 | 313 | 1 | 0.32% | ||
| HDAC2 | 2258 | 4 | 0.18% | ||
| NANOG | 6594 | 11 | 0.17% | ||
| CTCF | 2604 | 2 | 0.08% | ||
| PRC2 | 5660 | 3 | 0.05% | ||
| c-JUN | 31052 | 15 | 0.05% | ||
| NKX2 | 4338 | 1 | 0.02% | ||
| LHFPL4 | 11 | 0 | 0.00% | ||
| CELF6 | 14 | 0 | 0.00% | ||
| LHFPL3 | 21 | 0 | 0.00% | ||
| EVX2 | 40 | 0 | 0.00% | ||
| FOXB1 | 42 | 0 | 0.00% | ||
| PRDM13 | 47 | 0 | 0.00% | ||
| ZIC5 | 68 | 0 | 0.00% | ||
| CELF4 | 92 | 0 | 0.00% | ||
| LARP1 | 95 | 0 | 0.00% | ||
| DLX6-AS1 | 107 | 0 | 0.00% | ||
| ZIC4 | 107 | 0 | 0.00% | ||
| OTP | 109 | 0 | 0.00% | ||
| DBX1 | 112 | 0 | 0.00% | ||
| IRX1 | 121 | 0 | 0.00% | ||
| NRN1 | 135 | 0 | 0.00% | ||
| GRIK2 | 154 | 0 | 0.00% | ||
| POU3F2 | 160 | 0 | 0.00% | ||
| SNX1 | 167 | 0 | 0.00% | ||
| NR2E1 | 174 | 0 | 0.00% | ||
| TLX3 | 174 | 0 | 0.00% | ||
| VSX2 | 198 | 0 | 0.00% | ||
| TBX18 | 210 | 0 | 0.00% | ||
| OTX1 | 243 | 0 | 0.00% | ||
| TCF12 | 263 | 0 | 0.00% | ||
| SALL1 | 296 | 0 | 0.00% | ||
| ZIC2 | 323 | 0 | 0.00% | ||
| SIX2 | 336 | 0 | 0.00% | ||
| HOXA13 | 349 | 0 | 0.00% | ||
| NEUROg2 | 374 | 0 | 0.00% | ||
| EGR3 | 412 | 0 | 0.00% | ||
| FOXD3 | 420 | 0 | 0.00% | ||
| OBI1-AS1 | 650 | 0 | 0.00% | ||
| PHOX2B | 718 | 0 | 0.00% | ||
| NEUROD1 | 987 | 0 | 0.00% | ||
| PAX2 | 1720 | 0 | 0.00% | ||
| PAX5 | 2007 | 0 | 0.00% | ||
| TWIST1 | 2555 | 0 | 0.00% | ||
| SON | 5576 | 0 | 0.00% | ||
| REST | 1828 | 0 | 0.00% | ||
| TF t(ransferrin) | 4126 | 0 | 0.00% | ||
mitochondria |
|||||
| c-JUN | 31052 | 1231 | 3.96% | ||
| TF t(ransferrin) | 4126 | 67 | 1.62% | ||
| ZIC1 | 313 | 5 | 1.60% | ||
| NANOG | 6594 | 79 | 1.20% | ||
| HDAC2 | 2258 | 26 | 1.15% | ||
| NEUROD1 | 987 | 10 | 1.01% | ||
| FOXD3 | 420 | 4 | 0.95% | ||
| SIX2 | 336 | 3 | 0.89% | ||
| NKX2 | 4338 | 33 | 0.76% | ||
| SNX1 | 167 | 1 | 0.60% | ||
| TWIST1 | 2555 | 15 | 0.59% | ||
| PAX2 | 1720 | 10 | 0.58% | ||
| TLX3 | 174 | 1 | 0.57% | ||
| PRC2 | 5660 | 28 | 0.49% | ||
| TBX18 | 210 | 1 | 0.48% | ||
| OTX1 | 243 | 1 | 0.41% | ||
| TCF12 | 263 | 1 | 0.38% | ||
| OBI1-AS1 | 650 | 2 | 0.31% | ||
| CTCF | 2604 | 8 | 0.31% | ||
| EGR3 | 412 | 1 | 0.24% | ||
| SON | 5576 | 9 | 0.16% | ||
| PAX5 | 2007 | 3 | 0.15% | ||
| REST | 1828 | 2 | 0.11% | ||
| LHFPL4 | 11 | 0 | 0.00% | ||
| CELF6 | 14 | 0 | 0.00% | ||
| LHFPL3 | 21 | 0 | 0.00% | ||
| EVX2 | 40 | 0 | 0.00% | ||
| FOXB1 | 42 | 0 | 0.00% | ||
| PRDM13 | 47 | 0 | 0.00% | ||
| ZIC5 | 68 | 0 | 0.00% | ||
| CELF4 | 92 | 0 | 0.00% | ||
| LARP1 | 95 | 0 | 0.00% | ||
| DLX6-AS1 | 107 | 0 | 0.00% | ||
| ZIC4 | 107 | 0 | 0.00% | ||
| OTP | 109 | 0 | 0.00% | ||
| DBX1 | 112 | 0 | 0.00% | ||
| IRX1 | 121 | 0 | 0.00% | ||
| NRN1 | 135 | 0 | 0.00% | ||
| GRIK2 | 154 | 0 | 0.00% | ||
| POU3F2 | 160 | 0 | 0.00% | ||
| NR2E1 | 174 | 0 | 0.00% | ||
| VSX2 | 198 | 0 | 0.00% | ||
| SALL1 | 296 | 0 | 0.00% | ||
| ZIC2 | 323 | 0 | 0.00% | ||
| HOXA13 | 349 | 0 | 0.00% | ||
| NEUROg2 | 374 | 0 | 0.00% | ||
| PHOX2B | 718 | 0 | 0.00% |
1. Insect Genes vs. Mitochondria-Hit Genes
A. Insect Genes That Do Appear in the Mitochondria List
From the papers you provided (e.g., “Primordial Pathways” and Horvath’s insect‐presence table), the following transcription factors/homeobox genes are shared with the mitochondria‐hits list:
- c‐JUN (3.96% in the mitochondria list)
- ZIC1 (1.60%)
- FOXD3 (0.95%)
- NKX2 (0.76%)
- TBX18 (0.48%)
- PRC2 (0.49%)
These overlap genes are important in both insect development (e.g., wing or neural patterning in Drosophila) and mammalian mitochondrial/oxidative stress pathways, suggesting a deep evolutionary link.