Molecular Basis for Longevity

"Molecular Signatures of Longevity : Insights from Cross-Species Comparative Studies".

Seminars in Cell & Developmental Biology (07 Aug 2017) 70:190-203

Table 1

"Putative lifespan-related traits and other features associated with longevity in exceptionally long-...-lived species".


Notable features / putative lifespan-related traits

Naked mole rat

  • Early contact inhibition mediated by high-molecular-mass hyaluronan.

  • Cryptic intron in 28S ribosomal RNA; high translational fidelity of ribosome.

  • Unique amino acid changes in proteins involved in cell cycle and DNA integrity.

  • Early stop codons in p16Ink4A and p19Arf transcripts. Produce unique pALTInk4a/b with greater capacity for cell cycle arrest. Naked mole rat p19Arf induces cell cycle arrest but produces less cell death than mouse p19Arf

  • Low expression of genes involved in insulin/IGF1 signaling in liver; unconventional expression of IGF2 and IGFBP2 in liver and sequence changes in insulin β-chain.

  • Upregulation of genes associated with oxidation-reduction and mitochondria.

  • Augmented activities of Nrf2 (by reducing Nrf2 degradation).

  • Fructose-driven glycolysis supporting resistance to hypoxia.

Blind mole rat

  • Concerted cell death induced by interferon β secretion.

  • p53 protein with an amino acid change corresponding to mutation associated with human tumors; reduced interaction with coactivator p300 and DNA repair protein RPA70.

  • Weakened apoptotic function of p53 to favor reversible cell cycle arrest.

  • Unique splice variant of heparanase with anti-tumorigenic properties.

  • Unique amino acid change in Keap1 protein at position important for Nrf2 binding and degradation.

African elephant

  • One canonical TP53 copy and 19 additional forms with disrupted ORFs that may have originated from retro-transposition.

  • Peripheral blood lymphocytes show measurable TP53 retrogene expression and Mdm2 binding and undergo higher rate of apoptosis when exposed to radiation.

  • Estimated to be twice as sensitive to DNA damage-induced apoptosis as human cells.

Table 2

"Summary of key findings from recent cross-species comparative studies".

Cross-species studies

Key findings

Transcripts (33 mammalian species, 3 organs)

  • Positive correlation with lifespan: base-excision repair, nonhomologous end joining, regulation of immune response, regulation of defense response.

  • Negative correlation with lifespan: lipid oxidation, fatty acid metabolism, amino acid degradation, tricarboxylic acid cycle, mitochondrial respiratory chains, and ubiquitin complex.

Transcripts (15 mammalian species, fibroblasts)

  • Positive correlation with lifespan: DNA repair, nucleotide binding, glucose metabolic process, chromosome organization.

  • Negative correlation with lifespan: proteolysis, protein transport and localization, regulation of transcription, apoptosis regulation.

  • Fibroblasts of long-lived species were more resistant to stress-inducing agents such as cadmium and paraquat.

Metabolites (26 mammalian species, 4 organs, 262 metabolites)

  • Positive correlation with lifespan: sphingomyelins, urate:allantoin ratio.

  • Negative correlation with lifespan: amino acid, lysophosphatidyl-cholins, lysophosphatidyl-ethanolamines, triacylglycerols with polyunsaturated fatty acid, anthranilic acid and kynurenine.

Elements (26 mammalian species, 4 organs, 18 elements)

  • Positive correlation with lifespan: zinc (but largely body mass dependent), cadmium (may due to passive accumulation along food chain).

  • Negative correlation with lifespan: selenium.

Lipids (35 mammalian species, 6 organs, 13,000–21,000 compounds)

  • Predictors of longevity (after adjusting for other confounding factors): high levels of triacylglycerols, low levels of glycerophospholipids and sphinoglipids.

  • Number of double bonds associated with lifespan variations, but the effects dependent on the lipid classes.

  • Enzymes linked to these lipid classes and pathways displayed signatures of greater stabilizing selection in long-lived species.

Cross-species metabolome, ionome, and lipidome

"Gene expression is informative with regard to molecular features associated with longevity across species, but this is only one of the ways to assess these features. Two studies reported the analyses of metabolite and ion levels in brain, heart, kidney, and liver of 26 mammalian species across 10 taxonomic orders (Ma et al., 2015a; Ma et al., 2015b). Among the 162 water soluble metabolites and 100 lipids, positive correlation with species longevity traits was observed for sphingomyelins (in brain), whereas negative correlation was observed for amino acids (in brain), lysophosphatidyl-cholines (in brain and heart), lysophosphatidyl-ethanolamines (in brain and kidney), and triacylglycerols (in kidney) (Ma et al., 2015b). In particular, only those triacylglycerols with polyunsaturated fatty acid (PUFA) side chains showed significant negative correlation with species lifespan. A recent study on human plasma lipidomes of middle-aged offspring of nonagenarians revealed a signature of 19 lipid species associating with female familial longevity, including high levels of sphingomyelins and low levels of PUFA triacylglycerols (Gonzalez-Covarrubias et al., 2013). Analysis of phospholipids in heart of a number of mammals also revealed a negative correlation between double bond content and maximum lifespan (Pamplona et al., 2000). Naked mole rat tissues contain much lower levels of docosahexaenoic acid-containing (with 6 double bonds) phospholipids compared to mouse (Mitchell et al., 2007). Since PUFA are particularly sensitive to peroxidation damage (especially when present in membrane) (Hulbert, 2008), reduced level of polyunsaturated TAG in long-lived species may reflect their enhanced resistance to oxidative stress. Indeed, the peroxidation index for membrane composition is inversely correlated to longevity in mammals, birds, bivalve mollusks, honeybees and C. elegans (Hulbert et al., 2014).

In addition, high urate:allantoin ratio was observed among the long-lived species, which also expressed lower levels of uricase in liver (the enzyme that converts urate to allantoin). In fact, the uricase expression levels were exceptionally low in the naked mole rat, and this gene is a pseudogene in human and other higher primates (Ma et al., 2015b). The liver concentrations of two tryptophan degradation products, anthranilic acid and kynurenine, were also low among the long-lived species. Knockdown of the enzyme involved in breaking down tryptophan (tryptophan 2,3-dioxygenase, TDO) was shown to increase lifespan in C. elegans and fruit flies (Oxenkrug, 2010; van der Goot et al., 2012), whereas the kynurenine:tryptophan ratio in human increases with aging (Capuron et al., 2011).

In the ionome study, the levels of 18 elements in brain, heart, kidney and liver samples of the mammals were quantified by inductively-coupled plasma mass spectrometry. Each organ showed a distinctive pattern of ion distribution: lithium, sodium, and calcium levels were relatively high in kidney; phosphorus and potassium were high in brain; and 13 out of the 18 elements were high in liver (Ma et al., 2015a). In terms of correlation with longevity, zinc in kidney and liver showed significant positive correlation with species lifespan, although the effect was largely due to body mass."