Telomere Length:a 21st century Biomarker

DR UNA FAIRBROTHER

What is in the nucleus of each human cell ?

Material of inheritance Genetic material

composed of DNA and proteins

condensed to form chromosomes

Nucleosome structure DNA structure

Subunit of chromatin composed of a short length of DNA wrapped around a core of histone proteins

Linker DNA

The functional units: Genes

Genetic information, or "genes,” are a series of bases called adenine (A), guanine (G), cytosine (C), and thymine (T).

These base pairs make up the sequences, or instructions needed to form proteins, our cellular machinery.

What is a human telomere?

Telomeres are DNA-protein complexes found at the ends of chromosomes,

They protect functional regions (containing genes) by capping the ends with a “buffer” sequence.

Like the hem of a curtain. When they are completely worn

away, the cell is destroyed. Telomeres consist of variable numbers

of a repetitive sequence, (TTAGGG)n, Telomeres are stabilised by the aptly

named protein complex, shelterin (de Lange, 2005).

Telomeres shorten with each cell division, in most body or “somatic” cells,

This is largely a result of the way the linear DNA replicates (Olovnikov 1973),

Telomerase

Telomere shortening is mitigated by an enzyme called telomerase (in some cell types).

It elongates chromosomes by adding TTAGGG sequences to the end of existing telomeres.

Telomerase is found in fetal tissues, adult germ cells, and also tumor cells.

All rapidly dividing cells

Telomere length: why do we care?

Significantly, telomere length is positively correlated with human lifespan (Kimura et al., 2008).

Telomere length influenced by stress

Premature telomere shortening leads to premature aging of cells.

It can be caused by environmental stress factors including: socioeconomic status (SES), diet,

exercise and adverse life events, HIV

All the adverse conditions are associated with and/or oxidative damage.

Telomere shortening and environment

This process can be accelerated abnormally by oxidative stress. (von Zglinicki 2002, Kurz et

al., 2004). Oxidative stress is an

imbalance between the production of free radicals and the ability of the body to remove their harmful effects.

Connection between factors that may influence telomere length

Inheriting telomere length in humans

A variety of environmental factors result in humans having individual variation in telomere length.

BUT recent research has highlighted the heritability of telomere length, estimated at 70%

(Broer et al., 2013) Thus if you have shorter telomeres to

start with you may be more likely to suffer adversely from accelerated cellular aging.

Obesity and Diabetes induces oxidative stress

Telomeres are rich in guanine which is sensitive to oxidative damage

Telomeric oxidative damage can both alter shelterin binding and inhibit the telomerase activity important in early life.

Thus telomere dysfunction, rather than just telomere DNA shortening may be the trigger for cell aging. (Buxton et al., 2011).

The mechanisms are largely unknown, although obesity (like smoking) induces increased oxidative stress.

Furthermore, high levels of plasma oxidative stress are correlated with shorter telomeres in people with T2D (Klelia et al., 2010).

Future health and telomere length

Educational attainment, nutrition in infancy and childhood, exercise patterns, sleep patterns, socioeconomic factors, racism, unemployment and chronic psychological stress have all also been associated with shorter telomere length.

All these factors will accelerate cellular aging (Epel et al., 2004, Valdes et al., 2005,

Steptoes et al., 2011, Drury SS, et al., 2012, Jackowska et al., 2012, Ala-Mursala et al., 2013, Fujishero et al., 2013, García-Calzón et al., 2013, Needham et al., 2013),

Socio-economic status (SES) in Caucasians

Low SES status increases early morbidity and mortality.

Commonly-used measures of SES include: education, income, wealth, occupational

prestige. How can this be possible? Low SES is associated with stress: financial strain, hazadarous home and

work environments, less access to psychosocial resources (Alder and Stewart 2010, Needham et al.,

2013).

Telomere length is associated with low SES in African children

In African-American children, exposure to stress including low income and unstable family environment has recently been reported to be associated with reduced telomere length by age 9 (Mitchell et al., 2014).

Gene: environmental interactions may differ significantly between different ethnic groups

but few studies been carried out in other ethnicities (Needham et al., 2013)

Nutritional environment is also important

In women, there is evidence that production of oestrogen is a risk factor for obesity (related to length of reproductive years of life) and greater telomere and lower telomerase

activity. We can successfully intervene A recent study showed improvement in obesity

after a 5-year Mediterranean diet intervention along with an increase in telomere length (Parks et al., 2011, García-Calzón et al., 2013, ( de Vos-Houben et al., 2013).

Common disease

Both shorter telomere length (and its inverse: higher telomerase activity) have been associated with a variety of common diseases e.g. breast and colon cancer, type

2 diabetes (T2D), cardiovascular disease, hypertension, dementia and blastocyst aneuploidy

(Adaikalakoteswari et al., 2005, Brouilette et al., 2007, Fitzpatrick et al., 2007, Yang et al., 2009, Salpea et al., 2010, Wentzensen et al., 2011, Codd et al., 2013, Ornish et al., 2013, Roger et al., 2013, Zhu et al., 2013, Mania et al., 2014, Qin et al., 2014).

Which cells can we study?

There are robust correlations between telomere length in a number of tissues, buccal cells, skin epithelia, synovial

tissue, peripheral lymphocytes, vascular wall and umbilical artery

There are tissue differences, BUT relative telomere length is tissue

independent This means that correlation found in

different tissues can be used to predict telomere length in others. (Ocuda et al., 2002, Aviv, 2008, Wilson

et al., 2008, Gadalla et al., 2010, Wong et al., 2011)

Telomere length as a Biomarker

Once telomeres become critically short, DNA damage responses are activated, triggering aging in cells.

Very easily and robustly measured via fluorescent PCR

Can be done in many different cells ie cheek cells

Burning questions

Who is more/most susceptible to premature telomere shortening?

What are the risk factors? How can we mitigate them? Telomere length may prove key

in predicting the future health of children and young people

Our research: Telomere length as a biomarker Colombian Children

Columbian Hispanics are an understudied population

Despite Colombia being a middle-high income country there remains high socioeconomic inequality and rising mortality from non-communicable disease, which disproportionately affects the lower socioeconomic groups:

biomarkers in these groups would be particularly useful to identify key factors in development of disease risk (Arroyave et al., 2014).

We are examining this population to establish which childhood exposures have the greatest effect on telomere length and potentially on future health

Aims and collaborators

In an innovative project, we will measure telomeres in Colombian Hispanic children and compare them to detailed life events including a novel index of stress score.

No other study has investigated all targeted parameters in a population from the same age group.

Identifying factors associated with telomere shortening in comparable low-income groups where poor nutrition, low physical activity and environmental stress in childhood, is common.

This work has the potential to be of high impact and makes use of cross discipline thinking.

I am working with Dr Walley, St Georges, Dr Buxton, UCL and Prof Blakemore, Imperial College London.

In summary

We have described DNA structure In the nucleus Explained telomere structure Discussed the importance of telomere length Explored the impact of telomere length on human

health Decribed the exciting research being done to

develop telomere length as a useful bio marker.