Sirtuin Evolution at the Dawn of Animal Life

Abstract

Sirtuins are a family of proteins that protect against cellular injury and aging; understanding their evolution should reveal fundamental mechanisms governing longevity. “Early-branching” animals such as sea sponges and jellyfish have been understudied in previous analyses of sirtuin diversity. These organisms not only hold important positions at the base of the evolutionary tree, but also have unique aging dynamics that defy convention, such as quasi-immortality and high regenerative capacity. In this study, we survey the evolution of sirtuin proteins in animals, with a focus on the oldest living lineages. We describe previously unrecognized expansions of “Class IV” and “Class I” sirtuins around the origin of animals, raising the number of sirtuin families in the last common ancestor to at least nine. Most of these undescribed sirtuins have been lost in vertebrates and other bilaterian animals. Our work also clarifies the evolution of PNC1 and NAMPT, enzymes that carry out the rate-limiting step in sirtuin-related NAD+ biosynthesis. The genes for PNC1 and NAMPT enzymes were both present in the first animals, with the genes being lost a minimum of 11 and 13 times respectively over the course of animal evolution. We propose that species with these ancestral gene repertoires are ideal model organisms for studying the genetic regulation of animal longevity and will provide clues to increasing longevity in humans.

How Many Sirtuin Genes Are Out There? Evolution of Sirtuin Genes in Vertebrates With a Description of a New Family Member

“…2 ). A diversity of phylogenetic arrangements for sirtuin genes have been proposed in the past ( Frye 2000 , 2006 ; Greiss and Gartner 2009 ; Slade et al 2011 ; Vassilopoulos et al 2011 ; Costantini et al 2013 ; Scholte et al 2017 ; Simó-Mirabet et al 2017 ; Yang et al 2017 ; Rajabi et al 2018 ; Kabiljo et al 2019 ; Zhao et al 2019 ; Gold and Sinclair 2022 ), and our results largely support the relationships proposed by Frye (2006) .…”

“…2 ). The sister-group relationship between SIRT6 and SIRT7 has been recovered in all examined studies ( Frye 2000 ; North and Verdin 2004 ; Greiss and Gartner 2009 ; Hirschey 2011 ; Slade et al 2011 ; Vassilopoulos et al 2011 ; Costantini et al 2013 ; Scholte et al 2017 ; Simó-Mirabet et al 2017 ; Yang et al 2017 ; Rajabi et al 2018 ; Kabiljo et al 2019 ; Zhao et al 2019 ; Gold and Sinclair 2022 ), suggesting that there is robust support for the sister relationship between these sirtuin family members. In the third clade, there is a broad consensus in the literature that SIRT2 shares a common ancestor more recently in time with SIRT3 than with any other sirtuin paralog, and that the clade containing SIRT1 sequences is sister to the SIRT2/SIRT3 clade ( Frye 2000 , 2006 ; North and Verdin 2004 ; Greiss and Gartner 2009 ; Hirschey 2011 ; Slade et al 2011 ; Vassilopoulos et al 2011 ; Costantini et al 2013 ; Scholte et al 2017 ; Simó-Mirabet et al 2017 ; Yang et al 2017 ; Rajabi et al 2018 ; Zhao et al 2019 ).…”

“…2 ). Evolutionary relationships between these two family members are still a matter of debate, as a variety of phylogenetic positions have been suggested for these paralogs ( Slade et al 2011 ; Vassilopoulos et al 2011 ; Costantini et al 2013 ; Yang et al 2017 ; Rajabi et al 2018 ; Gold and Sinclair 2022 ), and only in a fraction of the studies their sister-group relationship is supported ( Frye 2000 , 2006 ; North and Verdin 2004 ; Greiss and Gartner 2009 ; Hirschey 2011 ; Scholte et al 2017 ; Simó-Mirabet et al 2017 ; Kabiljo et al 2019 ; Zhao et al 2019 ). In the second clade, we recovered SIRT6 sister to the clade containing SIRT7 sequences with strong support ( fig.…”

“…The evolution of the sirtuin genes is an active area of investigation. There are multiple phylogenetic hypotheses describing evolutionary relationships among the orthologs and paralogs in the sirtuin gene family ( Frye 2000 , 2006 ; North and Verdin 2004 ; Greiss and Gartner 2009 ; Pereira et al 2011 ; Slade et al 2011 ; Vassilopoulos et al 2011 ; Costantini et al 2013 ; Scholte et al 2017 ; Simó-Mirabet et al 2017 ; Yang et al 2017 ; Rajabi et al 2018 ; Kabiljo et al 2019 ; Zhao et al 2019 ; Gold and Sinclair 2022 ). Differences in the taxonomic sampling, number of orthologs and/or paralogs included, and the inclusion of outgroups are likely contributors to this variation.…”

Systematic Insight of Resveratrol Activated SIRT1 Interactome through Proximity Labeling Strategy

“…The sirtuin family encodes class III histone deacetylases (HDACs), which are homologous to the Saccharomyces cerevisiae transcription regulator Sir2 [ 1 ]. Mammalian sirtuins SIRT1-7 are nicotinamide adenine dinucleotide (NAD) + -dependent deacetylases [ 2 ] that are widely distributed in cells with different subcellular localizations.…”