The most important genes/proteins/enzymes for aging

The two most important classes of proteins are the long-lived structural proteins and the repair ones (DNA repair, breakdown ones [autophagy and proteostasis - , still trying to look up membrane repair]).

ERCC1, proteasome genes (esp beta7 subunit), chaperone-mediated autophagy genes (eg LC3)

20S proteasome catalytic subunit β5

19S proteasome subunit PSMD11/Rpn6 [25, 28, 103], which is an essential subunit for the activity of the 26S/30S proteasome that stabilizes the otherwise weak interaction between the 20S core and the 19S cap

Rpn11 overexpression suppresses the age-dependent reduction of 26S/30S proteasome activity and extends lifespan of flies [118]. In addition, increased levels of Rpn11 suppress expanded PolyQ-induced progressive neurodegeneration [118]. In C. elegans, overexpression of Rpn6 is sufficient to extend longevity under proteotoxic stress conditions and reduces toxic aggregates in PolyQ-disease models [17]. Increased assembly of active proteasomes induced by overexpression of the 20S proteasome subunit β5 confers resistance to oxidative stress and delays senescence in human fibroblasts

For example, catalase, superoxide dismutases, peroxiredoxins, thioredoxins, glutaredoxins, glutathione, glutathione peroxidases, and methionine sulfoxide reductases all represent families of enzymes that have evolved to directly or indirectly cope with harmful ROS and thereby mitigate potentially damaging nonenzymatic modification to macromolecules (Meyer et al., 2009, Muller et al., 2007).

(B and C) In an analogous manner, oxidative stress and nitrosative stress cause the oxidation (B) and nitrosylation (C) of protein residues, respectively. These damaging nonenzymatic protein modifications are removed by methionine sulfoxide reductases (MsrA,B) and thioredoxins (Trx) or the S-nitrosoglutathione reductase (GSNOR) system, which preserve protein function and support cellular health.

glyoxylase I and II enzyme system, which serves to detoxify intracellular glycation-inducing dicarbonyl compounds such as methylglyoxal

basically “repair” genes many upregulated by NRF2
SIRT6 (more than the other sirtuins - vera says it’s the ONLY one that increases longevity)

In Drosophila, flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies.[13][14]

telomerase genes: (ALT, WRN helicase, Rad52, ku67, POT, Shelterin, TRF1) [important but not central]

list of bowhead whale and naked mole rat genes with highest dN/dS values

dopamine genes (DAT, D2/D4)

MAYBE on FGF21 - High FGF21, Low Insulin And Glucose: A Pro-Longevity Strategy? - YouTube

thioredoxin

Slightly important but not critical for longevity

REST protein

An intriguing observation is that the autophagic vacuoles identified by LC3-mCherry were virtually all positive for LAMP1, a marker of late endosomes and lysosomes, indicating that dendrites mainly contain autolysosomes and no or very few autophagosomes (LC3-positive and LAMP1-negative) and late endosomes/lysosomes (LC3-negative and LAMP1-positive). One is left wondering if it results from LC3 overexpression and overflooding to interconnected organelles

Knowledge of the Wallerian degeneration mechanism has been transformed by the identification of genetic mutations that delay it by ~10-fold. The identification of Wallerian degeneration slow (Wlds), a mutant fusion protein, revealed a key role for NAD-related metabolism (438). Based on this, a wild-type NAD synthesizing enzyme, NMNAT2, was shown to be lost rapidly after axotomy and essential for axon survival (247). When NMNAT2 expression is constitutively blocked, axons fail to grow beyond a short distance, and if knocked down after axons have grown, these axons degenerate through the Wallerian pathway (246). In essence, removing NMNAT2 spontaneously activates the Wallerian pathway even without injury. NMNAT2 matches many of the properties of the ‟neuronal trophic substanceˮ postulated by Lubinska

From Horvath 2021 paper, the strongest hypermethylation sites with age:

LHFPL4/LHFPL3 genes (strongly hypermethylated with aging and we still don’t know WHY)

Also hypermethylated: TLX3, EVX2, NEUROD2, ZIC2 (all TFs), CELF6, PAX2, BDNF, PAX5, NRN1, PRDM13, OTP, NEUROD1

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(it’s suspected that these hypermethylated sites don’t matter as much as the hypomethylated sites, even though the strongest age associations happen for these hypermethylated sites). Methylation accelerates the most during early development, and sure while SOME aging happens then, it’s not the critical kind of aging that reduces performance.

membrane/lipid repair maybe? https://www.nature.com/articles/s41467-019-12483-0

except this are to acute injury rather than, say, oxidized lipids in the membrane

[SIRT6 Positively Affects The Hallmarks Of Aging And Extends Lifespan]

(SIRT6 Positively Affects The Hallmarks Of Aging And Extends Lifespan - YouTube)

modifications that lack protein quality control:

Other nonenzymatic reactions involving metabolites are implicated in disease but lack known quality-control or detoxifying mechanisms. Similar to the mechanism of protein glycation in diabetes, prolonged elevation of cyanate in the blood of smokers or during renal failure can cause harmful nonenzymatic protein lysine carbamylation (Figure 2B) (Flückiger et al., 1981, Stark, 1965). Excessive protein carbamylation may be a common mechanism underlying the pathophysiology of inflammation and coronary artery disease (Wang et al., 2007).

Separately, recent work has demonstrated that the glycolytic metabolite and acyl-phosphate 1,3-bisphosphoglycerate (Figure 2) can nonenzymatically modify protein lysine residues by virtue of its highly reactive electrophilic carbonyl carbon (Moellering and Cravatt, 2013). This novel modification, 3-phosphoglyceryl-lysine, was further shown to impair the activity of select glycolytic enzymes but is not yet associated with any disease states.

More commonly, drug toxicity is often caused by electrophilic drug metabolites nonenzymatically reacting with cellular proteins, and minimizing this problem is one of the foremost challenges during the development and optimization of small-molecule pharmaceuticals (Evans et al., 2004, Horng and Benet, 2013). Interestingly, the reactivity and toxicity of many drug metabolites is dependent on their bioactivation to acyl-CoA thioesters (Sallustio et al., 2000). Collectively, these studies demonstrate that nonenzymatic reactions of endogenously generated metabolites with cellular proteins contributes to the pathophysiology of diabetes, neurodegeneration, kidney failure, inflammation, coronary artery disease, and drug toxicity.

favorite summary of the supercentenarian genes paper

Latest News

Living Beyond 100 Years

Mayka Sanchez, PhD
UIC Barcelona

It is not my case, but some people have grandparents that lived beyond 105 and even beyond 110 years! These people are named semi-supercentenarians and supercentenarians, respectively. Healthy aging and exceptional longevity (people who live more than 100 years) are deeply related, as clinical and biochemical data on centenarians showed that they can be considered as a paradigm of healthy aging as they avoid or largely postpone all major age-related diseases.

You (and other scientists) may ask yourself: How do they manage to live for so many years? Is it the good weather, enough exercise, good wine… is it in their GENES?

Genetic variability on human extreme longevity is supported by the fact that individuals surviving to the age of 105 have a chance to have a sibling surviving to that age of 35 times greater than the control population. Therefore, some genetic factors should contribute to this trait. However, longevity is a complex trait for which gene-environment interactions (that are population-specific) as well as the complex interplay of multiple genes and pathways play a major role. Therefore, well controlled studies should incorporate individuals with well-advanced age (more than 105 years old) and controls in a homogenous population all matched for geographical origin.

This is exactly what has been done by Italian scientists, including some belonging to our society, to have some answers to the genetic contribution on extreme longevity. They shared what they found in an e-LIFE article.

Whole-genome sequencing analysis of semi-supercentenarians. Elife. 2021 May 4;10:e57849. doi: 10.7554/eLife.57849. PMID: 33941312; PMCID: PMC8096429.

In this work, the authors generated and analyzed the first Whole Genome sequencing (WGS) data with high coverage (90X) in a cohort of 81 semi-supercentenarians and supercentenarians [105+/110+] recruited across the entire Italian peninsula together with a control cohort of 36 healthy geographically matched individuals. In addition, the use recently published data (Giuliani et al., 2018b) as a second independent cohort of 333 centenarians (>100 years) and 358 geographically matched controls to replicate their results. The aim of this study was to identify the genetic determinants of extreme longevity in humans.

The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load in semi-supercentenarians if compared to younger healthy controls).

The authors found that in their WGS association study five SNP common variants were the top association signals. Those SNPs are located in the same large block of linkage disequilibrium at chromosome 7 containing STK17A, COA1 and BLVRA genes. One of these five variants, rs10279856, may play a regulatory role in the region. The SNP rs10279856 seems to play a pleiotropic role as it is an eQTL for STK17A gene and for two other genes (COA1 and BLVRA).

The most frequent alleles in 105+/110+ people (rs10279856-G reference allele and rs3779059-A, rs849166-A, rs849175-A alternative alleles) were associated with an increase in SKT17A gene expression in heart and other tissues, reduced expression of COA1 gene in several tissues and increased expression of BLVRA in whole blood, while reduced expression in artery and esophagus.

STK17A gene, Serine/Threonine Kinase 17a (Apoptosis-Inducing), is involved in DNA damage response and positive regulation of apoptotic process (Sanjo et al., 1998) and regulation of reactive oxygen species (ROS) metabolic process. Overall, the authors’ findings indicate that aging and longevity might be due to an increase in SKT17A expression due to the presence of favorable genetic variants in supercentenarians, by a mechanism which maintains DNA damage responses, favoring healthy aging.

COA1 gene is a component of the MITRAC complex (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) that regulates cytochrome c oxidase assembly. MITRAC complexes regulate both the translation of mitochondrial-encoded components and the assembly of nuclear-translation of mitochondrial-encoded components and the assembly of nuclear-encoded components imported in mitochondrion and in particular the respiratory chain complexes I and IV. Authors do not address why the reduced expression of COA1 gene due to the most frequent alleles present in supercentenarians influences healthy aging. However, it is known that apoptosis is regulated by the redox state of cytosolic cytochrome c (a heme containing protein), that is oxidized by mitochondrial cytochrome c oxidase (COX, also referred to as complex IV).

Therefore, new exploratory roles are open to study how oxidative stress is prevented or less deleterious in supercentenarian people. Now we know that mitochondria are not only necessary for ATP generation, but it seems that mitochondrial dynamics have a crucial role for human longevity and health.

More to say about redox status and longevity…

The protein encoded by the BLVRA (Biliverdin reductase A) gene belongs to the biliverdin reductase family, members of which catalyze the conversion of biliverdin to bilirubin. Recently, it has been established that a redox cycle based on BLVRA activity provides physiologic cytoprotection as BLVRA depletion exacerbates the formation of reactive oxygen species (ROS) and increase cell death. Interestingly, BLVRA contributes significantly to modulation of the aging process by adjusting the cellular oxidative status (Kim et al., 2011). Moreover, Biliverdin reductase A was previously shown to regulate the inflammatory response to endotoxin, by inhibiting Toll-like receptor 4 (TLR4) gene expression (Wegiel et al., 2011). How low levels of BLVRA in whole blood of supercentenarians exactly contribute to longevity is a question that remains to be explored.

Finally, in this article it was also shown that supercentenarians individuals are characterized by a lower prevalence of somatic mutations in six out of seven genes involved in hematopoietic malignancies. Therefore, it seems that not only a good genetic signature in DNA repair mechanisms is needed for longevity but also clonal haematopoiesis is a crucial player for healthy aging.

Overall, living beyond 100 years seems to be a game in which our cells should escape from mutations impairing the function of genes involved in stress response and DNA repair, to avoid accumulation of DNA damage and to delay age-related decline. But if your cells cannot do that, do not worry too much as one can say in Italian: “Non c’é male che duri cent’anni” and you would be dead by that time (I mean in 100 years from now).

Take care. :slightly_smiling_face:

Mayka Sanchez
BioIron Secretary

posted: May 25, 2021