translational research that have the potential to dela y or conc eivab ly p reve nt most such disord ers. Howe ver , ther e is a cave at that requ ires more thorough investigation: the degree to which in- terventions that retard aging and delay the on- set of age-related disorders will be accompanied by a com pressi on of morbidit y. In other words , will such inte rven tion s regu larl y lead to an in- crease in the ratio of health span to life span? Will our medi cate d cent enar ians lead fulf illi ng liv eswitheve ntual sudden collap se, or will they suffer from proportionally protracted durations of chronic disease? Although some research on cent enari ans sugg ests a compr essio n of morbi dity (

14

)

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and rap amy cin , in par tic ula r, app ear s to dis - prop orti onat ely enha nce many mea sure s of heal th span in mice (

15

)

—

future progress in geroscience interventions will nee d to be carefully monitored.

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ACKNOWLEDGMENTS

Geroscience in our laboratories and the labs of others at the University of Washington is supported by the Nathan Shock Center of Excellence in the Basic Biology of Aging, NIA grant P30AG013280. 10.1126/science.aad3267

REVIEW

Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection

Elizabeth H. Blackburn,

1

*

Elissa S. Epel,

2

Jue Lin

1

Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type

–

specific fashion. T elomere mainte nance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.

T

he telomere is a highly regulated and dy- namic complex at chromosome ends, con- sis tin g of a tra ct of tan dem ly re pea te d sho rt DNA repe ats and asso ciat ed prot ect ive pro- teins (Fig. 1) (

1

). The tel ome re pro tec ts thegenom ic DNAthrou gh vari ous mechan isms . One funct ion is to preve nt the end of the linear chromosomal DNA from bein g recog nize d as a broken end . This preven ts processes

—

suc h as DNA end-jo ini ng, DNA recomb ination , or DNA repair

—

tha t woul d lea d to unstable chromosomes. The general chromo- somal DNA repl ication mac hinery cannot c om- pletely copy the DNA out to the extr eme end s of the linea r chrom osome s. Over the cours e of cell di- vis ion s, thi s le adsto at tri tio n of chr om oso me en ds. This deficiency can be resolved in eukaryotes by the cel lula r ribo nuc leo pro tei n enz ymet elomerase, whic h can add tel om eri c repe at sequ en ce s to the ends of chromosomes, hence elongating them to compensate for their attrition (

2

). Other damage-cau sing mecha nisms can also contribute to telomer e-shorten ing processe s; these include nuclease action, chemical (such as oxi- dative) damage, and DNA replication stress. To offs et thes e var ious proc ess es, tel omer ase, as well as rec ombi nat ion betw een telo meri c repe ats, can act to replenish telomere length (

3

). In many human cell types, the levels of telo- merase (or of its action on telomeres) are limit- ing, and in hum ans , tel ome res shor ten thr oug hout the lif e sp an. The deg re e of sho rte ni ng is rou gh ly proportionate to risks of common, often comor- bid, diseases of aging as well as mortality risk. Inherited telomere syndromes (

4

,

5

) have been highly informative for dissecting the roles and interactions of telomere maintenance defects in the general population

’

s human aging and age-relate d diseases. Declining telomere main- tenance has pathophysiological effects on cells that can lie upstream of, as well as interact with, a number of the cellular hallmarks of aging (

6

). Bec aus e the eff ect s of com pro mis ed tel ome re mai n- tenance in humans play out in cell- and tissue- specific ways, they consequently differ between

SCIENCE

sciencemag.org

4 DECEMBER 2015

•

VOL 350 ISSUE 6265

1193

1

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.

2

Department of Psychiatry, University of California, San Francisco, CA 94143, USA.

*Correspondin g author . E-mail: elizabeth.blackbu rn@ucsf .edu

Chromosome Telomere Single stranded DNA-binding protein complexes Single stranded DNA overhang 5’ 3’ Repeated G-rich double-stranded DNA sequence 5’ Shelterin proteins

Fig. 1. T elomere structure.

The human telomere complex consists of a chromosomal-terminal tract of a tandemly repeated DNA sequence bound by prote ctiv e shelt erin compon ent prote ins, with addi- tional protective proteins on the overhanging single- stranded end region of the telomeric DNA repeat. This simplified schematic does not indicate details of the protein structures or of the architecture of the telomeric complex.