Telomere Changes in Vivo with Age
Telomere changes in vivo with age
Nan-ping Weng
Laboratory of Molecular Biology and Immunology
National Institute on Aging, NIH Telomere changes in vivo with age
1. Overview of telomere and its function
2. Telomere length changes in lymphocytes in vivo with age.
3. Factors influencing telomere length change in vivo with age.
4. Consequence of shortened telomeres of lymphocytes in the elderly Telomere and Telomerase
150-200 nt Telomere
TRF1 TRF2
TTAGGG TTAGGG
AATCCC AATCCC 5-10 kb Telomerase
T loop
Chromosome Strand invasion of the G-strand overhang 5’ D loop 3’OH Telomere/Telomerase Hypothesis
Germ cells Telomerase Lymphocytes Active Inactive
Tumor cells length Telomere Somatic cells
Cell division Telomere attrition in granulocytes and lymphocytes with age
Lansdorp Blood 2007 Telomere states and its consequence
Closed-state DNA damage response and chromosome fusions
Intermediate-state Cell-cycle arrest ATM/p5 P53 loss 3 and senescence Continued cell division Uncapped-state Chromosome breakage, genomic instability, crisis. Features of T cell response and aging
E M E E IL-15 E N N E E E E N E M E E N N E E E E E
N M M M M M E N + E N M M M E
CD28+ CD28- Baltimore Longitudinal Study of Aging (BLSA)
• BLSA is supported and conducted by The National Institute on Aging (NIA), NIH, which begun in 1958 and is the longest-running scientific study of human aging in US.
• BLSA has more than 1,400 men and women voluntary participants. The age range of the participants is from 20s to 90s. • BLSA participants get a thorough free physical exam and medical tests every 1-5 years depending on their age. Summary of the BLSA participants in the study (216 over ~5 years and 171 ~12 years lifespan)
Age group Young Middle Old (≤40) (≥41, ≤70) (≥71)
Starting age 33 ± 5 53 ± 9 81 ± 5 Number 31 42 143 Gender (M, F) 14, 17 20, 22 80, 63 Year span 4-7 4-7 4-7 Experimental design
PBMCs (~216 BLSA participants) (2-3 samples with ~5 and ~12 years apart of each person) Telomere attrition with age (cross-sectional view)
PBMC T cell
B cell Monocyte Telomere length (mTRF, kb) (mTRF, length Telomere
Age Telomere length difference in blood cells
Telomere (kb) length
PBMC T cell B cell Monocyte Rate of telomere change in vivo
) yr PBMC T cell B cell Monocyt
bp / e length ( elomere
Rate of Age
On average, ~30% subjects showed loss of telomere, ~50% showed no obvious loss of telomere, and ~10% showed an increase of telomere length. Telomere length changes over 5- & 12-years Rate of telomere loss in different age groups Developmental regulation of Telomerase expression in T cells
Bone Marrow Thymus Periphery
+ - + CD4 8 + CD4 CD4
CD34+ CD4-8- CD4+8+
+ CD4-8+ CD8 CD8+
Precursor cells Thymocytes Resting T cells
Telomerase ++++ ++++ ++++ +++ +/- Activity
Decline of telomerase activity with age
Telomerase activity Telomerase
Age Correlation of telomere length and telomerase Correlationtelomere and length of
Telomerase activity Telomere length(kb) activity
Correlation of telomere length with telomerase activity, percent of naïve T cells, glucose and IL-6
Model 1 Model 2 Model 3 Model 4
Age -0.61 ±0.04* -0.54 ±0.04* -0.47 ±0.05* -0.40 ±0.07*
Sex (Male) -0.19 ±0.08 -0.26 ±0.08* -0.19 ±0.09
Telomerase activity 0.16 ±0.04* 0.23 ±0.04* 0.16 ±0.07*
Naïve T cell (%) 0.23 ±0.07*
Glucose -0.01 ±0.005*
IL-6 -0.05 ±0.03*
R-squared 0.38 0.39 0.45 0.43
* P<0.05 Selection criteria for long and short telomere healthy old
– HLA A-2+
– Age 70 and older
– In good health condition
– Telomere length of PBMC to top 1/3 (>6.2 Kb, n=10) and bottom 1/3 (<5.6 Kb, n=8) Experimental design of flu-vaccination
Pre- Post- Post- vaccination vaccination vaccination blood blood collection blood collection Collection (vaccine response) (memory response) (base line)
Day 0 21 84
40 ml blood were drawn at each visit Assessing the immune response
1. Antigen Presentation (APC) Function: A typical adaptive Isolate monocytes (CD14+), induce to APCs and test immune response their effectiveness to induce flu-specific CD8 cell proliferation. APC (DC)
2. B Cell function: a) Measure serum anti-flu antibody titers before and CD4 CD8 after vaccination; Killer cells b) Telomere length of B cells
3. T Cell function:
B-cell Antibody a) Flu-specific (M1) CD8 T cell expansion in response to M1-APC; b) Telomere length of M1-sepcific CD8 T cells
Anti-flu antibody titers correlated with B cell telomere length Flu-specific (M1) CD8 T cell response Short telomere group Long telomere group
Pre- Post- Pre- Post-
Counts
Flu-specific M1+ CD8 T cells Flu-specific (M1) CD8 T cell response Length of telomere is a determining factor of proliferation of M1-specific CD8 T cells in response to Ag
Ag-induced proliferation Telomere length Summary
1. Telomere length changes in lymphocytes and monocytes were dynamic in vivo with age (decrease, no change, and increase). Decrease is a dominant trend over longer time.
2. Reduction of telomerase activity in resting lymphocytes occurred after 70 years old, and reduction of induced telomerase activity was only found in T cells not in B cells.
3. Multiple factors contributed to telomere length changes in T cells with age including telomerase activity, percent of naïve and CD28- T cells, and health conditions (glucose and IL-6).
4. Individuals whose B cells with long telomeres had higher titers of anti-flu antibodies than individuals whose B cells with short telomeres. M1- specific CD8 T cells with long telomeres of had more proliferation than cells with short telomeres. Acknowledgements Weng lab, NIA, NIHTGB , NIA, NIH EIB, NCI, NIH
Guobing Chen Luigi Ferrucci Richard Hodes Jie Wan Kim Jeffrey Meter Jeffrey Chiang Michael Patrick Linda Zukley Christina Slota Johns Hopkins Medical School Jaekwan Kim Clinical lab, NIA, NIH Sean Leng Alvin Shi Julie McKelvey Huifen Li Ana Lustig Sandy Alcorta Kevin Najarro Melissa Lewis Johns Hopkins Medical School Huy Nguyen Jonathan Schneck Yun Lin Mathias Oelke Amanda Damjanovic Funding from NIA and NIAID