Epigenetics of aging

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Epigenetics refers to changes in characteristics, called phenotypes, passed to new cells which do not come from changes in the DNA sequence.[1] These characteristics can be transferred when the body generates new tissue. Such changes stem from molecular alterations which influence gene activity. The changes in gene activity resulting from epigenetic modifications can alter protein production.

DNA, chromatin, and histones

Chromatin consists of DNA wrapped around proteins called ‘histones.’ Eight histones, an octamer, conglomerate with DNA wrapped around the histones to form a nucleosome. A nucleosome, contains H2A, H2B, H3, and H4 histone proteins. DNA wraps around an H1 histone to form ‘linker DNA’ between nucleosomes.

Chromatin structures

Aggregations of DNA and histone proteins organized into nucleosomes form molecular structures called ‘chromatin’ in the ‘nucleus’ of cells. Loosely compacted chromatin, called ‘euchromatin,’ contains more active DNA in comparison to densely compacted chromatin, ‘heterochromatin,’ which is mostly inactive. Genes from DNA in euchromatin undergo a process called ‘transcription,’ where DNA is copied to RNA via an enzyme, RNA polymerase. Ribosomes, proteins in the aqueous ‘cytoplasm’ outside of the cell nucleus, then synthesize proteins based on the RNA in a process termed ‘translation.’

DNA modifications

One major DNA modification occurring in the nucleus of cells is ‘DNA methylation.’ Methylation consists of adding a methyl group (-CH3) to DNA, which usually inhibits DNA transcription and translation, also referred to as inhibiting ‘gene expression.’ This DNA modification, methylation, often occurs in regions of the DNA where transcription starts, promoter regions. Methylation of promoter regions typically blocks attachment of proteins called ‘transcription factors,’ thereby preventing transcription and subsequent protein production through translation.

Histone modifications

Molecular tags can modify histones. These tags include methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation. These molecular tags on histones influence chromatin compaction and influence what genes get transcribed to RNA and then translated to proteins.

Epigenetics and aging

Aging manifests as a reduction of normal functions of the body over time. Aging is important to human health due to increased susceptibility to diseases like cancer, metabolic disorders, heart disorders, and neurological disorders.[2] Causes of aging remain poorly understood, but scientists continue to try to acquire knowledge of the molecular pathways involved. In search of molecular hallmarks of aging, scientists have found epigenetic alterations, representing a crucial cellular mechanism of declining cell function with age.[2]

The chromosomes containing DNA carry genetic information, while the epigenetic modifications provide the functional use and stability of this information.[2][3][4][5][6] Epigenetic changes are reversible and can occur spontaneously or from external or internal influences.[2] Epigenetics could serve as the missing link in explaining why aging patterns differ between genetically identical twins or between genetically identical queen and worker bees.[7][8][2][9] Studies of longevity show genetic factors could explain 20% to 30% of the differences between life spans of identical twins; however, most of the remaining differences are thought to come from epigenetic changes throughout life.

Different environmental influences, such as diet, cause changes in stored epigenetic information and striking differences in physical appearance, reproductive behavior, and lifespan of worker and queen honeybees. This results despite the bees having identical DNA content.[2][10]

Given enzymes establish epigenetic modifications, epigenetic information is reversible. Due to this reversibility, epigenetics holds prospects for therapeutic intervention targeting. This stands in contrast to genetic changes, which are not technically reversible in humans.[2] Understanding epigenetic changes occurring during aging is therefore a major area of study, which could pave the way for new therapeutic methods of delaying aging and diseases caused by aging.

Types of epigenetic information

Encoded in the epigenetic information, termed ‘epigenome,’ is information in the form of presence or absence of histones on particular DNA sequences, DNA methylation, chromatin, remodeling, modifications of the histone proteins (posttranslational modifications), functional and structural variants of histones, and noncoding RNAs.[7][11][5][2] These factors play crucial roles in determining the function of cells and tissues. Each of these types of epigenetic information plays an essential role in the process of aging.

Evidence suggests chromatin structure, carrying much of the epigenetic information, has a major role during aging. The basic unit of the chromatin structure, the nucleosome, consists of 147 base pairs of DNA wrapped around a histone octamer with eight subunits. With the addition of linker histones, like H1 between nucleosomes, higher order structures of chromatin repressing gene activity, such as heterochromatin, can be formed. Organizing DNA into highly organized chromatin structures regulates gene activity.

Mechanisms of aging based on epigenetics

The process of aging is quite complex. Aging cells undergo numerous changes and accrue damage. Evidence continues to accumulate showing cellular processes affecting aging act primarily through epigenetic modifications. Without a doubt, epigenetic influences over aging need to be incorporated into the current understanding of processes of aging.

The heterochromatin loss model of aging

The “heterochromatin loss model of aging” suggests a loss of heterochromatin ensues with aging, leading to expression of genes lying in regions of heterochromatin. According to the model, this loss of heterochromatin causes aging and loss of cellular functions.

Global histone protein reduction during aging

Not only has heterochromatin reorganization during aging been observed but a loss of histone proteins from chromosomes during aging has also been found. This has been shown as a cause of aging in yeast.[2] The histone protein loss observed in yeast has also been observed in aging worms[12][2] and in human cells.[13][14][2] Loss of histone proteins in aged cells could cause inappropriate access to genetic material and subsequent gene activity.

Genomic instability resulting from chromatin relaxation during aging and the “aging by transposition” model

Chromatin in a looser state due to heterochromatin loss or histone loss could induce transcriptional dysfunction and also instability of chromosomes. Reduced histone proteins in old yeast led to more DNA breaks and insertions of DNA in inappropriate areas of the DNA sequence.[2] DNA damage can drive organismal aging.

Histone variant changes with aging

Histones which are distinctly different from core histones regulate chromatin. Age-associated changes for these “variant” histones are greater than for the core histones. For example, histone H3.3 is a histone H3 variant which incorporates with chromosomes whether or not DNA replication occurs. When cells are no longer dividing in older age, the H3.3 histone incorporates excessively in chromatin to drive aging in cells.[2]

Histone modification changes during aging

Histones of chromatin undergo a variety of modifications, such as methylation or acetylation. These modifications enable the regulation of the use of DNA sequences for gene activity, called gene expression. Histone modifications can reduce chromatin organization or provide binding surfaces to the DNA sequence so they can recruit other proteins to regions of the chromatin. The array of histone modifications orchestrates functional responses, which are diverse and which are incompletely understood. These responses regulate gene transcription, DNA repair, DNA replication, condensation of chromatin, and other events which affect processes, including aging.[2]

Nucleosome remodeling and aging

The cell regulates nucleosome alterations to contribute to processes of DNA expression. Mutations of nucleosome remodelers in cells have been associated with several age-related diseases and cancers.[2][15][16]

DNA methylation changes and aging

DNA methylation is perhaps the most studied and characterized epigenetic marker during aging.[2][17] Stretches of DNA within and between genes have repeats of bases called ‘CpG’ repeats. The ‘C’ represents the cytosine base, the ‘p’ represents the phosphodiester backbone of DNA, and the ‘G’ represents the guanine base. These repeated stretches can undergo methylation. In young cells, most CpG stretches throughout all DNA, the genome, have methylation. This methylation leads to repressed activity of genes and compact chromatin structures, like heterochromatin. Genes with high activity, highly expressed genes, do not have much DNA methylation and are called ‘CpG islands.’ DNA methylation is important in development, where it silences gene expression in tissues where their activity will not be needed.

During aging of identical twins, DNA methylation patterns become more different when compared to each other. These differences come from ‘epigenetic drift,’ which causes epigenetic differences from environmental factors or spontaneous errors in processes of DNA methylation pattern transmission.[2][18] Epigenetic drift causes differences in methylation patterns between people which cannot be predicted. Some methylation changes with age involve specific regions of the genome. These DNA methylation changes during aging could be associated with cellular mechanisms of the aging process.

In mammals, aging is more commonly associated with reduced methylation of CpG stretches of DNA. This is probably partly responsible for heterochromatin loss during aging. The decrease in DNA methylation with aging may also come from reduced levels of the enzyme which methylates DNA, DNMT1.[2][17]

Non-coding RNAs and aging

Contrasting with earlier beliefs, it is widely accepted now that about 60 to 90% of the human genome is transcribed.[19][2][20] This gives rise to a substantial array of non-coding RNAs. Non-coding RNAs have epigenetic effects and have significant influence on altering gene expression and chromatin packing. A complete understanding of the many biological functions of non-coding RNAs has yet to be understood.[21][2][22] Disrupting non-coding RNA function has been associated with diseases such as cancer, neurological disorders, heart disorders, and aging.[23][24][2]

Transgenerational epigenetic changes affecting aging

Biological dogma says genetics dictates inherited traits across generations. This dogma has been challenged with evidence of epigenetic inheritance in the production of gametes, eggs and sperm cells. Scientists made these observations in flower color and symmetry in plants and coat color and size in mice.[25][26][2] Longevity has recently been shown to be epigenetically inherited for several generations due to histone methylation.[2] This implicates, for the first time, epigenetic inheritance across generations in regulating lifespan.

Lifespan-extending methods functioning partly through epigenetic changes

Altering epigenetic information has attracted attention as a promising way to extend lifespan, because epigenetic changes can be modulated with manipulating relevant enzymes. Epigenetic interventions altering epigenetic information hold the potential to extend lifespan and combat age-associated diseases like cancer and neurological disorders.

The most readily available means to extend lifespan is dietary restriction. This method involves limiting the number of calories an organism consumes. This method has profound effects in many organisms, including yeast, flies, worms, mice, and primates.[2] Evidence suggests epigenetic alterations, including DNA methylation and histone modifications, may be crucial in lifespan extension with dietary restriction.[27][28][2]

Metformin, an antidiabetic drug, induces effects similar to dietary restriction.[2][29] A recent study involving more than 180,000 people showed diabetes patients treated with metformin lived longer than other diabetic patients and also lived longer than healthy adults in the study.[30][2] Another recent report provided evidence metformin’s mechanism of action occurs through epigenetic regulation. Increased levels of SIRT1 were observed with metformin treatment in human subjects.[2][31] SIRT1 is involved in preserving chromosome stability, repairing damaged DNA, and cellular health maintenance.

References

  1. ↑ Y Li, M Daniel, TO Tollefsbol.  Epigenetic regulation of caloric restriction in aging. BMC Med, 2011; 9: 98.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 Sangita Pal, Jessica K Tyler.  Epigenetics and aging.  Sci Adv, 2016; DOI: 10.1126/sciadv.1600584.
  3. ↑ AD Goldberg, CD Allis, E Bernstein.  Epigenetics: A landscape takes shape.  Cell, 2007; 128: 635-638.
  4. ↑ U Munoz-Najar, JM Sedivy.  Epigenetic control of aging.  Antioxid Redox Signal,  2011; 14: 241-259.
  5. ↑ 5.0 5.1 RJ O’Sullivan, J Karlseder.  The great unravelling: Chrommatin as a modulator of the aging process.  Trends Biochem, 2012; 37: 466-476.
  6. ↑ L Zane, V Sharma, T Misteli.  Common features of chromatin in aging and cancer: Cause or coincidence?  Trends Cell Biol, 2014; 24: 686-694.
  7. ↑ 7.0 7.1 A Brunet, SL Berger.  Epigenetics of aging and aging-related disease.  J Gerontol A Biol Sci Med Sci, 2014; 69 (Suppl. 1): S17-S20.
  8. ↑ MF Fraga, E Ballestar, MF Paz, S Ropero, F Setien, ML Ballestar, D Heine-Suner, JC Cigudosa, M Urioste, J Benitez, M Coix-Chornet, A Sanchez-Aguilera, C Ling, E Carlsson, P Poulsen, A Vaag, Z Stephan, TD Spector, Y-Z Wu, C Plass, M Estellar.  Epigenetic differences arise during the lifetime of monozygotic twins.  Proc Natl Acad Sci, 2005; 102: 10604-10609.
  9. ↑ M Sargent.  Why twins age differently.  Nature, 2010; 464: 1130-1131.
  10. ↑ R Kucharski, J Maleszka, S Foret, R Maleszka. Nutritional control of reproductive status in honeybees via DNA methylation.  Science, 2008; 319: 1827-1830.
  11. ↑ J Feser, J Tyler.  Chromatin structure as a mediator of aging.  FEBS Lett, 2011; 585: 2041-2048.
  12. ↑ Z Ni, A Ebata, E Alipanahiramandi, SS Lee. Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans.  Aging Cell, 2012; 11: 315-325.
  13. ↑ A Ivanov, J Pawlikowski, I Mmanoharan, J van Tuyn, DM Nelson, TS Rai, PP Shah, G Hewitt, VI Korolchuk, JF Passos, H Wu, SL Berger, PD Adams.  Lysosome-mediated processing of chromatin in senescence.  J Cell Biol, 2013; 202: 129-143.
  14. ↑ RJ O’Sullivan, S Kubicek, SL Schreiber, J Karlseder.  Reduced histone biosynthesis and chroatin changes arising from a damage signal at telomeres.  Nat Struct Mol Biol, 2010; 17: 1218-1225.
  15. ↑ GJ Narlikar, R Sundaramoorthy, T Owen-Hughes. Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes.  Cell, 2013; 154: 490-503.
  16. ↑ CR Clapier, BR Cairns.  The biology of chromatin remodeling complexes.  Annu Rev Biochem, 2009; 78: 273-304.
  17. ↑ 17.0 17.1 M Jung, GP Pfeifer.  Aging and DNA methylation.  BMC Biol, 2015; 13: 7.
  18. ↑ MF Fraga, E Ballestar, MF Paz, S Ropero, F Setien, ML Ballestar, D Heine-Suner, JC Cigudosa, M Urioste, J Benitez, M Coix-Chornet, A Sanchez-Aguilera, C Ling, E Carlsson, P Poulsen, A Vaag, Z Stephan, TD Spector, Y-Z Wu, C Plass, M Estellar.  Epigenetic differences arise during the lifetime of monozygotic twins.  Proc Natl Acad Sci, 2005; 102: 10604-10609.
  19. ↑ ENCODE Project Consortium et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.  Nature, 2007; 447: 799-816.
  20. ↑ JE Wilusz, H Sunwoo, DL Spector.  Long noncoding RNAs: Functional surprises from the RNA world.  Genes Dev, 2009; 1494-1504.
  21. ↑ FF Costa.  Non-coding RNAs: Meet thy masters.  Bioessays, 2010; 32: 599-608.
  22. ↑ TR Cech, JA Steitz.  The noncoding RNA revolution—Trashing old rules to forge new ones.  Cell, 2014; 157: 77-94.
  23. ↑ K Szafranski, KJ Abraham, K Mekhail.  Non-coding RNA in neural function, disease, and aging. Front Genet, 2015; 6: 87.
  24. ↑ M Esteller.  Non-coding RNAs in human disease.  Nat Rev Genet, 2011; 12: 861-874.
  25. ↑ EL Greer, TJ Maures, D Ucar, AG Hauswirth, E Mancini, JP Lim, BA Benayoun, Y Shi, A Brunet.  Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans.  Nature, 2011; 479: 365-371.
  26. ↑ JP Lim, A Brunet.  Bridging the transgenerational gap with epigenetic memory.  Trends Genet, 2013; 29: 176-186.
  27. ↑ K Szafranski, KJ Abraham, K Mekhail.  Non-coding RNA in neural function, disease, and aging. Front Genet, 2015; 6: 87.
  28. ↑ A Vaquero, D Reinberg.  Calorie restriction and the exercise of chromatin. Genes Dev, 2009; 23: 1849-1869.
  29. ↑ VN Anisimov.  Metformin: Do we finally have an anti-aging drug?  Cell Cycle, 2013; 12: 3483-3489.
  30. ↑ CA Bannister, SE Holden, S Jenkins-Jones, CL Morgan, JP Halcox, G Schernthaner, J Mukherjee, CJ Currie.  Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls.  Diabetes Obes Metab, 2014; 16: 1165-1173.
  31. ↑ SV de Kreutzenberg, G Ceolotto, A Cattelan, E Pagnin, M Mazzucato, P Garagnani, V Borelli, MG Bacalini, C Franceschi, GP Fadini, A Avogaro.  Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes.  A randomized controlled trial.  Nutr Metab, 2015; 25: 686-693.
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