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Most genetic roots of fungal and animal aging are hundreds of millions of years old according to phylostratigraphy analyses of aging networks

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Abstract

Few studies have systematically analyzed how old aging is. Gaining a more accurate knowledge about the natural history of aging could however have several payoffs. This knowledge could unveil lineages with dated genetic hardware, possibly maladapted to current environmental challenges, and also uncover “phylogenetic modules of aging,” i.e., naturally evolved pathways associated with aging or longevity from a single ancestry, with translational interest for anti-aging therapies. Here, we approximated the natural history of the genetic hardware of aging for five model fungal and animal species. We propose a lower-bound estimate of the phylogenetic age of origination for their protein-encoding gene families and protein–protein interactions. Most aging-associated gene families are hundreds of million years old, older than the other gene families from these genomes. Moreover, we observed a form of punctuated evolution of the aging hardware in all species, as aging-associated families born at specific phylogenetic times accumulate preferentially in genomes. Most protein–protein interactions between aging genes are also old, and old aging-associated proteins showed a reduced potential to contribute to novel interactions associated with aging, suggesting that aging networks are at risk of losing in evolvability over long evolutionary periods. Finally, due to reshuffling events, aging networks presented a very limited phylogenetic structure that challenges the detection of “maladaptive” or “adaptative” phylogenetic modules of aging in present-day genomes.

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Acknowledgements

We wish to thank Duncan Sussfeld, Cameron Osborne, and Dr. Johannes Martens for critical reading of the manuscript and comments. H.B. was funded by a grant from the Ministère de la Recherche; J.T. was funded by an Emergence grant from Sorbonne Université (S21JR31001—IP/S/V2 EMERG-ESPA) to E.B.

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Authors and Affiliations

  1. Institut de Systématique, Evolution, Biodiversité (ISYEB), Sorbonne Université, CNRS, Museum National d’Histoire Naturelle, EPHE, Université Des Antilles, Paris, France

    Hugo Bonnefous, Jérôme Teulière, Philippe Lopez & Eric Bapteste

  2. Département de Sciences Biologiques, Complexe Des Sciences, Université de Montréal, Montréal, QC, Canada

    François-Joseph Lapointe

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  1. Hugo Bonnefous
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  4. Philippe Lopez
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  5. Eric Bapteste
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Contributions

H.B., J.T., and E.B. designed the research; H.B. and J.T. performed the research; P. L. and E. B. contributed to the conceptualization, project administration, funding acquisition, and supervision; H.B., J.T., F.J.L., P. L., and E.B. analyzed the data; H.B., J.T., and E.B. wrote the paper; H.B. and J.T. contributed equally to this work. All authors read and approved the final manuscript.

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Correspondence to Eric Bapteste.

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Supplementary Information

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11357_2024_1234_MOESM1_ESM.pdf

Supplementary file1 Figure S1: Filtering of orthogroups based on sequence complexity. For each orthogroup (i.e., set of genes/proteins belonging to a ‘’rootHOG’’ as defined in OMA), the Shannon entropy of each sequence has been computed, as a proxy of sequence complexity. The resulting distribution of mean entropy per group (each dot representing an orthogroup present in at least one of the 5 species of interest) is left-skewed and was filtered to avoid potential artefactual groups of low-complexity. The red horizontal line indicates the threshold used for filtering low-complexity outliers (calculated mean sequence entropy of ~3.68). The blue and red dots represent orthogroups conserved or discarded by the filtering, respectively. (PDF 1733 KB)

11357_2024_1234_MOESM2_ESM.pdf

Supplementary file2 Figure S2: Constitution of orthogroups and functional orthogroups from OMA gene trees.The gene tree represents an illustrative toy ‘’rootHOG’’, simulating those provided by the OMA database in an orthoXML file. From there, an orthogroup is defined as a family containing any protein/gene on the tree, and the origin of the orthogroup is set to the last common ancestor of all contemporary species found in the leaves (here, the last common ancestor of Euarchontoglires, the smallest clade grouping Primates Homo sapiens - Pan troglodytes and Rodents Mus musculus – Jaculus jaculus). The ID of the orthogroup is the one of the rootHOG. At each duplication occurring in the tree (descending from the root), the children branches gain a suffix added to its ID (for instance, following the path from root to gene pt2 : ‘’1’’, then ‘’1.2’’, then ‘’1.2.1’’). The final ID of a protein/gene (on a leaf) thus defines its‘’functional orthogroup’’, and the origin of this functional orthogroup is set to the last ancestral duplication leading to this group. (PDF 73 KB)

11357_2024_1234_MOESM3_ESM.pdf

Supplementary file3 Figure S3: Cumulative plots representing the phylostratification of gene families related to hallmarks of aging in H. sapiens and M. musculus, using the AgingAtlas database. Cumulative plots corresponding to the phylostratigraphy of genes associated to hallmarks of aging, as recorded in the AgingAtlas database for (A) Homo sapiens and (B) Mus musculus. For each plot, The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to the species of interest. Phylogenetic origins of orthogroups (defined using the OMA database) are indicated for genes belonging to the Aging Atlas database (for hallmark annotations) or not (not hallmarks genes). A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of orthogroups from each category that appeared before a given time point. (PDF 120 KB)

11357_2024_1234_MOESM4_ESM.pdf

Supplementary file4 Figure S4: Cumulative plot representing the phylostratification of functional orthologous protein coding genes in S. cerevisiae. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this yeast. Phylogenetic origins of functional orthogroups encoding proteins with known interactions are indicated for aging genes (blue), including the subcategories ’pro-longevity genes’ (orange), ‘anti-longevity genes’ (burgundy red) and ‘uncharacterized genes’ (yellow), and for non-aging genes (black). The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of functional orthogroups from each category that appeared before a given time point. The ‘wave plots’ illustrate when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 62 KB)

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Supplementary file5 Figure S5: Cumulative plot representing the phylostratification of functional orthologous protein coding genes in M. musculus. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this mouse. Phylogenetic origins of functional orthogroups encoding proteins with known interactions are indicated for aging genes (blue), including the subcategories ’pro-longevity genes’ (orange), ‘anti-longevity genes’ (burgundy red) and ‘uncharacterized genes’ (yellow), and for non-aging genes (black). The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of functional orthogroups from each category that appeared before a given time point. The ‘wave plots’ illustrate when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 80 KB)

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Supplementary file6 Figure S6: Cumulative plot representing the phylostratification of functional orthologous protein coding genes in humans. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to humans. Phylogenetic origins of functional orthogroups encoding proteins with known interactions are indicated for aging genes (blue) and for non-aging genes (black).  The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of functional orthogroups from each category that appeared before a given time point. The ‘wave plots’ illustrate when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 67 KB)

11357_2024_1234_MOESM7_ESM.pdf

Supplementary file7 Figure S7: Cumulative plot representing the phylostratification of functional orthologous protein coding genes associated with cellular senescence in humans. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to humans. Phylogenetic origins of functional orthogroups encoding proteins with known interactions are indicated for aging genes (blue) and for non-aging genes (black).  The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of functional orthogroups from each category that appeared before a given time point. The ‘wave plots’ illustrate when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 69 KB)

11357_2024_1234_MOESM8_ESM.pdf

Supplementary file8 Figure S8: Cumulative plot representing the phylostratification of functional orthologous protein coding genes in D. melanogaster. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this fly. Phylogenetic origins of functional orthogroups encoding proteins with known interactions are indicated for aging genes (blue), including the subcategories ’pro-longevity genes’ (orange),‘anti-longevity genes’ (burgundy red) and ‘uncharacterized genes’ (yellow), and for non-aging genes (black). The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of functional orthogroups from each category that appeared before a given time point. The ‘wave plots’ illustrate when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 78 KB)

11357_2024_1234_MOESM9_ESM.pdf

Supplementary file9 Figure S9: Cumulative plot representing the phylostratification of functional orthologous protein coding genes in C. elegans. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this nematode. Phylogenetic origins of functional orthogroups encoding proteins with known interactions are indicated for aging genes (blue), including the subcategories ’pro-longevity genes’ (orange), ‘anti-longevity genes’ (burgundy red) and ‘uncharacterized genes’ (yellow), and for non-aging genes (black). The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of functional orthogroups from each category that appeared before a given time point. The ‘wave plots’ illustrate when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 71 KB)

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Supplementary file10 Figure S10: Robustness analysis: effect of sampling size on the mean distance of estimated phylostratigraphic curves to the reference one. For each species, 100 samples of size 5, 10, 25, 50, 100, 200, 500 and 1000 genes were randomly drawn among the total genome. For each sample size, the 100 associated phylostratigraphic curves were computed, and the mean distance between these curves and the complete genome phylostratigraphic curve was computed. The exact number of genes available for each species in the GenAge or CellAge databases are represented as vertical blue bars. (PDF 84 KB)

11357_2024_1234_MOESM11_ESM.pdf

Supplementary file11 Figure S11: Robustness analysis: effect of sampling size on the variability of estimated phylostratigraphic curves. For each species, 100 samples of size 5, 10, 25, 50, 100, 200, 500 and 1000 genes were randomly drawn among the total genome. For each sample size, we computed the 100 associated phylostratigraphic curves and the distance between each pair of curves. Then, the standard deviation of all these distances was computed. The exact number of genes available for each species in the GenAge or CellAge databases are represented as vertical blue bars. (PDF 84 KB)

11357_2024_1234_MOESM12_ESM.pdf

Supplementary file12 Figure S12: Cumulative plot representing the phylostratification of orthologous protein coding interactions in S. cerevisiae. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this yeast. Phylogenetic origins of genes are reported similarly to Fig. 1. Phylogenetic origins of edges representing protein interactions are indicated for aging edges (blue) and for non-aging edges (black). The Y-axis represents the cumulative proportion of edges from each category that appeared before a given time point. The ‘wave plots’ illustrate, from top to bottom, i) when aging edges that were associated to a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging edges from the same ancestry ; ii) the ratio of aging edges induced by aging nodes ; iii) the ratio of non-aging edges induced by non-aging nodes ; iv) the Rcn (aging edges/aging nodes)/(non-aging edges/non-aging nodes). (PDF 393 KB)

11357_2024_1234_MOESM13_ESM.pdf

Supplementary file13 Figure S13: Cumulative plot representing the phylostratification of orthologous protein coding interactions in humans. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to humans. Phylogenetic origins of genes are reported similarly to Fig. 2A. Phylogenetic origins of edges representing protein interactions are indicated for aging edges (blue) and for non-aging edges (black). The Y-axis represents the cumulative proportion of edges from each category that appeared before a given time point. The ‘wave plots’ illustrate, from top to bottom, i) when aging edges that were associated to a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging edges from the same ancestry ; ii) the ratio of aging edges induced by aging nodes ; iii) the ratio of non-aging edges induced by non-aging nodes ; iv) the Rcn (aging edges/aging nodes)/(non-aging edges/non-aging nodes). (PDF 1023 KB)

11357_2024_1234_MOESM14_ESM.pdf

Supplementary file14 Figure S14: Cumulative plot representing the phylostratification of orthologous protein coding interactions in D. melanogaster. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this fly. Phylogenetic origins of genes are reported similarly to Fig. 3. Phylogenetic origins of edges representing protein interactions are indicated for aging edges (blue) and for non-aging edges (black). The Y-axis represents the cumulative proportion of edges from each category that appeared before a given time point. The ‘wave plots’ illustrate, from top to bottom, i) when aging edges that were associated to a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging edges from the same ancestry ; ii) the ratio of aging edges induced by aging nodes ; iii) the ratio of non-aging edges induced by non-aging nodes ; iv) the Rcn (aging edges/aging nodes)/(non-aging edges/non-aging nodes). (PDF 1074 KB)

11357_2024_1234_MOESM15_ESM.pdf

Supplementary file15 Figure S15: Cumulative plot representing the phylostratification of orthologous protein coding interactions in C. elegans. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to this nematode. Phylogenetic origins of genes are reported similarly to Fig. 3. Phylogenetic origins of edges representing protein interactions are indicated for aging edges (blue) and for non-aging edges (black). The Y-axis represents the cumulative proportion of edges from each category that appeared before a given time point. The ‘wave plots’ illustrate, from top to bottom, i) when aging edges that were associated to a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging edges from the same ancestry ; ii) the ratio of aging edges induced by aging nodes ; iii) the ratio of non-aging edges induced by non-aging nodes ; iv) the Rcn (aging edges/aging nodes)/(non-aging edges/non-aging nodes). (PDF 684 KB)

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Supplementary file16 Figure S16: Cooption of mTOR during the evolution of the human aging network. Human protein-protein interaction subnetwork (STRING interactions with confidence score > 900) between MTOR (large central node) and its direct neighbors (small peripheral nodes). Nodes and edges were labelled by inferred phylogenetic age and colored as indicated. (PDF 937 KB)

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Supplementary file17 Figure S17: Cumulative plot representing the phylostratification of conserved gene families related to aging between H. sapiens and M. musculus (putative phylostratification of the last common ancestor of Euarchontoglires) Cumulative plots corresponding to the phylostratigraphy of conserved genes associated and non-associated with aging (genes recorded in the GenAge database) between H. sapiens and M. musculus. The X-axis reports a reference dating by phylostrata corresponding to ancestral nodes within the phylogenetic lineage leading to the last common ancestor of Euarchontoglires. Phylogenetic origins of orthogroups encoding proteins with known interactions are indicated for conserved aging genes (blue) and for conserved non-aging genes (black). The pie chart summarizes the number of genes in each category. A star (*) indicates when inferences of gene origination were impossible for a particular phylostratum due to limited phylogenetic coverage of the OMA database. The Y-axis represents the cumulative proportion of orthogroups from each category that appeared before a given time point. The ‘wave plot’ illustrates when aging genes from a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging genes from the same ancestry. (PDF 53 KB)

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Supplementary file18 Figure S18: Centrality of conserved aging genes in Euarchontoglires. Degree (left panels) and closeness (right panels) distributions were computed at gradually stringent STRING PPI score (score > 500, > 600, >700, > 800, > 900, or only with experimental support: exp) for conserved aging (pink boxes) and non-aging (cyan boxes) genes and for (A) M. musculus, (B) H. sapiens; (C) their inferred Euarchontoglire common ancestor’s networks. For each aging/non-aging comparison, aging genes were significantly more central than non-aging genes (unilateral Wilcoxon rank-sum test, p< 0.05 after correction for multiple testing using the Bonferroni method). (PDF 523 KB)

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Supplementary file19 Figure S19: Cumulative plot representing the phylostratification of inferred conserved ancestral proteic interactions in the ancestor of humans and mice. The X-axis reports a reference dating by phylostrata restricted to conserved nodes inferred to be present in the last common ancestor of humans and mice (Euarchontoglires). Phylogenetic origins of genes are reported similarly to Fig. S17. Phylogenetic origins of edges representing conserved ancestral protein interactions are indicated for aging edges (pink) and for non-aging edges (grey). The Y-axis represents the cumulative proportion of edges from each category that appeared before a given time point. The ‘wave plots’ illustrate, from top to bottom, i) when aging edges that were associated to a given ancestry accumulated proportionally less (ratio<1) or more (ratio>1) than non-aging edges from the same ancestry ; ii) the ratio of aging edges induced by aging nodes ; iii) the ratio of non-aging edges induced by non-aging nodes ; iv) the Rcn (aging edges/aging nodes)/(non-aging edges/non-aging nodes). (PDF 244 KB)

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Supplementary file20 Figure S20: Phylostatigraphic assortativity of complete and aging networks. Preferential interaction between similar nodes in networks is estimated by the assortativity coefficient. Assortativity coefficients were computed on nodes labelled by inferred phylogenetic age at six PPI stringency thresholds: (A) for proteins in the entire PPI networks; (B) for proteins associated with aging in the longevity networks of S. cerevisiae (Sc), D. melanogaster (Dm), C. elegans (Ce), M. musculus (Mm) and H. sapiens(Hs); or (C) for proteins associated with cell senescence in the senescence networks of H. sapiens. Several assortativity coefficients were significantly positive in node label permutation tests (stars, P < 0.05 after Bonferroni adjustment for multiple testing, for the species indicated below the data points, or for all species if no indication is given), indicating that proteins of the same inferred phylogenetic age tend to preferentially interact together in these networks. (PDF 47 KB)

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Supplementary file21 Table S1: Comparison of annotation content for databases listing hallmarks of aging related genes. The number of annotated genes used to analyze the phylostratification of hallmarks-related genes, coming from databases Open Genes (H. sapiens) and Aging Atlas (H. sapiens and M. musculus), is reported. For each hallmark annotation, the number indicates how many genes were used for our analyses (genes from the databases that have been successfully mapped to an OMA rootHOG of identified phylogenetic origin). (XLSX 10 KB)

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Supplementary file22 Table S2: Proportion of recycled old interactions in inferred ancestral longevity networks The proportions of inferredBilateria, Ecdysozoa and Euarchontoglires ancestral interactions in longevity networks (at all PPI stringency thresholds) with an inferred phylogenetic age strictly older than the ancestor (‘old ancestral interactions’), or of the same age as the ancestor (‘new ancestral interactions’) were calculated relative to all ancestral interactions with an inferred phylogenetic age. Values greater and lesser than expected by chance were determined by edge labels (age) permutation test, at a significance threshold of 0.05, after Bonferroni adjustment for multiple testing. NS: not significant.(DOCX 21 KB)

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Supplementary file23 Table S3: Size of the age-homogeneous components of PPI networks.The number, average size and size variance of connected components (CCs) formed by nodes with the same inferred phylogenetic age (phylogenetic modules) were computed in longevity networks composed of STRING interactions with a confidence score above 900 (PPI threshold: 900) or with experimental support score above 0 (PPI threshold : exp). CC size was either defined as the number of nodes or the number of edges, as indicated. Empirical p-values were calculated for the number of CCs, the mean CC size in edges and the mean CC size in nodes using node age label permutation tests, at a significance threshold of 0.05, after Bonferroni adjustment for multiple testing. These tests showed that all values were significantly lower than expected by chance. (XLSX 18 KB)

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Bonnefous, H., Teulière, J., Lapointe, FJ. et al. Most genetic roots of fungal and animal aging are hundreds of millions of years old according to phylostratigraphy analyses of aging networks. GeroScience (2024). https://doi.org/10.1007/s11357-024-01234-9

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