In As You Like It, Shakespeare has Rosalind tell us that “time travels in divers places with divers persons.” In Shakespeare’s era, the measurement of time was more fluid, less precise. Just as industrialization required the invention of ever more precise instruments to measure time, so have scientists concerned with the human life span sought a precise quantitative estimate of biological age. For reasons we shall discuss, the telomere has been proposed for this role. The study by Martens et al1 shows that the telomere lengths (TLs) of newborns (and their placentas) were associated with the social economic status (SES) of their parents. They argue that this finding could partially explain the well-known associations between SES, health, and longevity. To evaluate this idea, we should begin by understanding the role of the telomere in the life cycle of the cell.
Because humans and other eukaryotes have linear chromosomes, rather than the circular chromosomes of bacteria, our DNA confronts the end replication problem every time it is duplicated during cellular reproduction. The fact that DNA polymerase can only lay down new bases in 1 direction (from the 5′ to 3′ direction of the nascent strand) means that each cycle of replication will result in a shortening of the chromosome by approximately 50 base pairs. This is not sustainable, because genetic information would be lost with each cycle. One solution devised by nature is to terminate the chromosome tip with several thousand nucleotides of non-coding DNA—the telomere, which in vertebrates consists of multiple repeats (approximately 2500 in humans) of the sequence TTAGGG. The telomere can be construed as the sacrificial anode of the chromosome, becoming a bit shorter with each cellular reproductive cycle but protecting the vital subjacent genetic information. Most somatic cells, such as those that are sampled in blood or saliva, divide infrequently, and so this mechanism may suffice for the life of the organism. However, during development, in stem cells, and in rapidly proliferating tissues after fetal life, it may be necessary to counteract the reproductive shortening of telomeres. In these cells, the enzyme telomerase remains active and can lengthen telomeres; the contribution of telomerase to TL maintenance in routinely sampled tissues, such as blood or oral cells, is not clear but probably limited. Because these cells and the progenitor cells that give rise to them pass through the cell cycle, the measured length of their telomeres gradually decreases during a person’s life span, resulting in the idea that telomere length is a so-called mitotic clock or an indicator of biological age.
In landmark work nearly 2 decades ago, Epel et al2 found that the average TL was shorter than expected in individuals as the extent of caregiver stress increased. An association between stress or adversity and average TL of circulating blood or saliva cells has been repeatedly demonstrated in diverse contexts since the work of Epel et al,2 and many researchers have construed telomere shortening relative to chronological age as evidence of advanced biological aging, cellular aging, weathering, susceptibility to disease, and even a decreased potential life span.3,4 However, the complexity of this phenomenon is such that the biological mechanism of contextual telomere shortening is still not established, despite 2 decades of research. While it remains unclear whether TL shortening is simply a biomarker of stress or a biological mechanism that transfers stress-related signals to the cell, the evidence of an association is quite strong and extends to the association between TL and neighborhood as well as many individual sources of adversity or stress. The study by Martens et al1 bolsters this connection by providing evidence that this association begins before birth. In a sample of more than 1000 infants, an indicator of parental SES (based on the principle components of maternal and paternal education and occupation as well as neighborhood SES) was associated with cord-blood and placental TL in newborn boys but not girls; moreover, Martens et al1 suggest that this finding may provide a mechanism for the documented association between SES, health, and life span and could even serve as a transgenerational mechanism for transmitting the effects of stress. This study was large (1026 mother-infant pairs), well controlled, and clearly presented. Appropriate confounders that impose on the fetoplacental unit were identified.1 However, given the number of studies demonstrating associations between genetic propensity, educational and occupational attainment, and even the way people raise their children (ie, genetic nurturance), the design of the study1 does not exclude the possibility that the associations with TL were indirectly genetic as well as environmental.
Readers will have several questions about this research. First, are the TL measurements reliable; second, how does SES affect TL; third, is there a known link between TL and biological age; and finally, what does telomere homeostasis imply for future health and longevity?
While the measurement of TL by quantitative polymerase chain reaction is technically demanding,5 there is substantial interlaboratory variation, and the results of this method may differ from those obtained by Southern blot, cell sorting, or fluorescence in situ hybridization,6 the methods reported by Martens et al1 are robust and clearly described. They are likely reliable. Less clear is how readers should construe the negative association between SES and TL. There are plausible (albeit unproven) biological links between chronic stress and TL shortening. Also, as mentioned by the authors, this could involve stress-induced inflammation and oxidative damage to telomeres, suppression of telomerase by corticosteroid secretion or activation of the sympathetic nervous system, an increase in the proliferative index of the immune cells that are sampled in these studies, or a combination of these. From the perspective of biological mechanisms, one could conjecture that chronic stress increases as SES decreases, but this seems overly simplistic and even presumptuous. The authors1 also discuss cellular or biological age and associate shorter than expected telomeres with greater than expected biological age. However, biological age is a construct; it can be measured in several ways: by TL, certainly, but also by the extent of DNA methylation, by mitochondrial function or morphology, and by the accumulation of specific cellular proteins.7 Each approach provides a different estimate, and correlations are generally poor, implying that there is actually no unique biological substrate for the term biological age. Each measure likely points to different aspects of cellular life, such as the replicative history of a cellular lineage (TL), a developmental program (DNA methylation), environmental exposure or cellular toxicity (mitochondria and DNA methylation). Changes in these measures and health, well-being, or longevity probably represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (ie, stress, low SES, environmental toxicity) to the organismal effect (ie, cancer, vascular disease, shortened life span). While there is a temptation to interpret TL shortening as offering a biological mechanism to explain the well-described associations between adversity, wellness, and health, we should resist this temptation, at least until we know much more regarding the underlying biological mechanisms that drive these measurements. For now, modesty seems appropriate. We can conclude there is a very early (ie, at birth) association between SES and TL, and this is consistent with the observation that TL shortening (relative to the overall population) is associated with later declines in health and well-being. It is not clear what is added by postulating an intervening construct, such as biological age, to explain these findings.
Published: May 4, 2020. doi:10.1001/jamanetworkopen.2020.4352
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Notterman DA et al. JAMA Network Open.
Corresponding Author: Daniel A. Notterman, MD, MA, Department of Molecular Biology, Princeton University, 219 Lewis Thomas Laboratory, Princeton, New Jersey 08544 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Drs Notterman and Schneper reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant R01 HD076592) and the National Institute on Minority Health and Health Disparities.
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Notterman DA, Schneper L. Telomere Time—Why We Should Treat Biological Age Cautiously. JAMA Netw Open. 2020;3(5):e204352. doi:10.1001/jamanetworkopen.2020.4352
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