Telomere and aging

Claire FALANDRY, MD, PhDGeriatrics Unit, Lyon Sud Hospital, France

Lyon University, France

Conflict of interests

• None to declare

The telomere connection

Homologous recombinationNon Homologous End Joining

Replication fork stalling

High sensitivity to oxydative stress

End-replicationproblem

• 1938-9 : Muller -McClintock : telomere « telos » « meros »• 1961 : Hayflick Hypothesis (Mitotic clock)• 1973 : Olovnikov – A theory of marginotomy – the end-replication

p

y f m g my pproblem

• 1997 : Telomerase gene discovery• 1999 : Terc null mice display a premature aging phenotype p y p g g p yp• 2009 : Nobel prize pour E. Blackburn, C. Greider et J. Scoztack• 2011 : « telomere »: 13182 PubMed references

Telomerase activationALT telomere lengtheningChromosomal recombinations –telomere healing

SenescenceTissue renewal lossPro-inflammatory secretory phenotypePro-tumorogenic potential

Measuring telomere health ?

DNA damage response Senescence

60

DNA damage response signaling

- loss of telomerase activity ?- Higher turn over ?- Inflammaging ? - Oxydative stress ?Oxydative stress ?

PBMC length

• Mortality : controversial data:Cawthon RM & al: Association between telomere length in blood and mortality in people – Cawthon RM & al: Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003;361:393-5

– Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS, Tracy RP, Hardikar S, Aviv A: Leukocyte telomere length and mortality in the cardiovascular health study. J Gerontol A Biol Sci Med Sci 2011;66:421-9.

– Martin-Ruiz C & al: Assessment of a large panel of candidate biomarkers of ageing in the newcastle 85+ study. Mech Ageing Dev 2011;132:496-502.

– Eisenberg DT & al: Substantial variation in qpcr measured mean blood telomere lengths in young men from eleven european countries. Am J Hum Biol 2011;23:228-31.

– Willeit P & al: Telomere length and risk of incident cancer and cancer mortality Jama Willeit P & al: Telomere length and risk of incident cancer and cancer mortality. Jama 2010;304:69-75.

• Degenerative diseases :– Brouilette SW & al: Telomere length, risk of coronary heart disease, and statin treatment

in the West of Scotland primary prevention study: a nested case-control study. Lancet f p m y p y y2007;369:107–114

– van der Harst P & al: Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol 2007;49:1459–1464

– van der Harst P & al: Possible association between telomere length and renal dysfunction in patients with chronic heart failure Am J Cardiol 2008;102:207–210patients with chronic heart failure. Am J Cardiol 2008;102:207–210

Telomerase activity

• Epel ES & al: Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A 2004;101:17312-5.

• Atzmon G & al: Evolution in health and medicine sackler colloquium: Genetic variation in human telomerase is associated with telomere length in ashkenazi centenarians. Proc Natl Acad Sci U S A 2010;1:1710-7.

• Ornish D & al: Increased telomerase activity and comprehensive • Ornish D & al: Increased telomerase activity and comprehensive lifestyle changes: A pilot study. Lancet Oncol 2008;9:1048-57.

Telomere-dysfunction Induced foci (TIFs)( )

• Measuring directly DNA damage response

Augereau et al, Blood 2011From Gilson et al, Nat Rev Mol Cell Biol 2007

DNA-damage biomarkers

• Proteins induced by telomere dysfunction and DNA damage y yrepresent biomarkers of human aging and disease

Jiang et al PNAs 2008Jiang et al, PNAs 2008

Any clinical relevance of telomere analysis in oncogeriatrics ?analysis in oncogeriatrics ?

Metastatic

Feasibility

T tm t

ToxicitiesBenefit/

risk ratio

Treatment decision Expected

survival out of cancer

Adjuvant

Short

Long

f

term Toxicities

term Toxicities

GINECO’s experience

• 1999-2003 (FAG1) : CC treatment feasibility– 73 patients - Feasibility 72%

• 2004-2006 (FAG2): CP treatment feasibility2004 2006 (FAG2): CP treatment feasibility– 82 Patients - Feasibility 68%

• Multivariate analysis: negative impact of:– Age– Age– Depression and emotional disorders– Paclitaxel-based treatment

Stage (IV vs III)– Stage (IV vs III)• 2007-2010 (FAG3): C – Impact of emotional disorders

– Feasibility 74%

Working hypothesis

Other vulnerability

Old ageDepressionEmotional

factors ?

￬ telomere length ↓ telomerase

disorders

￬ telomere length ( = telomere attrition)

↓ telomeraseactivity

?

FAG 1 et FAG 2

Lymphocyte dysfunction

↓ Survival↑ Toxicities

Lymphopenia

Preliminary data of FAG3 study:telomere lengthm g

111 ti ts 111 bl d s li s

ALL (n=109)

- 111 patients, 111 blood samplings

7200

7700

8200ALL (n 109)

Short (n=36)

Linear

y = -25,934x + 8082,3R2 = 0,0326

5700

6200

6700

4700

5200

5700

420068 73 78 83 88 93

Short telomere are associated with a decreased feasibility of treatmenty

F ibilit f 6 C b l ti

60%70%80%90%

100%

p=0,0419

Feasibility of 6 Carboplatin coursesPts characteristics

Total (%) 111 (100)

Age (years)

Median 78

10%20%30%40%50%60%Median 78

≥ 80 45 (41)

Extremes 70-93

Performance status0%

LT ST

60%

p=0 0713Non hematological toxicities

0-1 63 (57)

2-3 48 (43)

≥ 1 dependance ADL 61 (55)

≥ 1 dependance on IADL 93 (75)

20%

30%

40%

50%p=0,0713≥ 1 dependance on IADL 93 (75)

Emotional disorders

Screening 20 (18)

HADS ≥ 15 41 (37)

0%

10%

LT ST

≥ 4 co-medications 76 (69)

And have a nearly significant impacton survival

1.0 ST5800=0

ST5800=1Long telomeres

Short telomeres.6

0.8 Median OS 13,5 vs 19,2mths

p=0,15

Sur

viva

l

0.4

00.

00.

2

• Multivariate analysis :– Stage (IV vs III) HR=2 53 (p=0 0004)

Time

0 10 20 30 40

Stage (IV vs III) HR 2,53 (p 0,0004)– Short telomeres HR=1,53 (p=0,09)

Towards a future challenge

Observational study of every elderly patient with

NOFIT patient: on going trialsevery elderly patient with

AOC assesses the pre-inclusion criteria

FIT patient: on-going trials

Standard Carboplatin AUC5 +

at least one “factor of vulnerability

Lymphopenia

YESVULNERABLE pts Single agent Carboplatin AUC 5R

pPaclitaxel 175mg/m² J1=J21, 6 cycles

-Lymphopenia-Albuminemia < 35g/l-≥ 1 ADL- IADL ≤ 27- emotional disorders

N = 240

Single agent Carboplatin AUC 5 J1=J21, 6 cycles

R

Weekly Carboplatin AUC2 + Paclitaxel 60mg/m² d1 d8 d15Biomarkers Paclitaxel 60mg/m² d1, d8, d15, J1=J28, 6 cycles

Biomarkers of aging