<Work in progress>
Then the LORD said, “My Spirit will not contend with humans forever, for they are mortal; their days will be a hundred and twenty years.” - Genesis 6:3 (New International Version)What scientists believe to be the maximum age of a human of about 120 years had been interestingly been documented in one of the earliest human texts, the book of Genesis, beliefs aside. Yet rarely any, if any, of us make it to that age.
The hard limit of 120 years, and not a statistical distribution that tapers off into longer ages, indicates there is a death program built into our cells. How to measure how quickly this program, or clock, has run?
Telomeres are the repetitive DNA sequences at the end of our chromosomes, which shorten with every cell division. At a critically short length the cell stops dividing and eventually dies with no replacement. In humans this is known as the Hayflick limit, after Dr Hayflick who noticed cultured human cells would only divide a maximum of 50 times.
In 2005 a 115-year-old women who died had donated her body to science provided some insights into extreme aging.
By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. “To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other,” said lead author of the study, Dr. Henne Holstege.White blood cells live for about three to four days in the average human body. If we make it past heart disease, cancer, neurological degeneration, then we might speculate that white blood cell stem cell exhaustion from critically short telelmores is what gets us all at the very end.
The authors also examined the length of the telomeres, or repetitive sequences at the ends of chromosomes that protects them from degradation. After birth, telomeres progressively shorten with each cell division. The white blood cell telomeres were extremely short -17 times shorter than telomeres in the brain. “Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from ‘stem cell exhaustion,’ reaching the upper limit of stem cell divisions,” said Holstege. Whether stem cell exhaustion is likely to be a cause of death at extreme ages needs to be determined in future studies. source
While telomere length could be a candidate for this hard limit, the biology of telomere length isn’t nearly as simple as what you might have been told, an not necessarily a good marker for aging. For starters is the existence of telomerase, an enzyme which rebuilds telomeres.
Unfortunately, the “telomere clock” did not keep time very well….it often ran too fast or could run in reverse with intervention or without intervention) (Hovatta, 2012). Part of this could be explained in terms of telomerase activation consequential to lifestyle modifications such as exercise, diet, or meditation. (Ornish, 2008) (Hoge, 2013). On an experimental level, major flaws in the “telomere clock theory” were found. A major one was the discovery that mice had long telomeres (50-150 kb) relative to human telomeres (15 kb), yet humans live as much as 50 times longer than mice (2 years vs 90-100 years) (Greider, 1996). If the “telomere clock theory” was correct, mice should outlive humans. The second flaw in the “telomere clock concept” was the discovery that mice expressed the enzyme telomerase, which should lengthen lifespan in mice to more than humans (Prowse, 1995). Instead, telomerase activation in mice appeared to contribute to their short lifespan since this increased the tendency of mice to form tumors (Due in part to the expression of telomerase, 90% of mice develop tumors during their lifespan). This lead to the theory that telomere shortening actually functioned as a tumor-suppressor mechanism which promoted organismal survival, but at the expense of getting old (Campisi, 2001).Discussed below methylation ‘clocks’ have shown to have a precision is higher than age predictions based on telomere length.
The 3rd major flaw in the “telomere clock concept” was the discovery that telomere shortening occurred with other cellular phenomena besides mitosis (i.e. cell division). For instance, radiation was found to shorten telomeres (Fritz, 2000). In addition, it was found that radiation could induce cell cycle arrest even if telomeres did not shorten (Suzuki, 2001). Ultraviolet light was found to shorten telomeres, with or without cell division (Oikawa, 2001). The same was found with chemotherapy and toxins (Engelhardt,1998) (Muller, 2006). The 4th major flow in the “telomere clock concept” occurred when it was discovered that oxidative stress accelerated telomere shortening and that telomere shortening could occur even in cells that were not dividing (Zglinicki, 2002). Since oxidative stress is a universal feature of aging, this meant that telomere shortening was an “effect” of aging, rather than the “upstream cause” of aging. As a result of these 4 major flaws in the telomere clock theory, as well as the incongruous evidence from the telomere lengths in mice and men, the theory that telomeres are accurate measures of biological age has largely been put to rest.
Glycans Are a Novel Biomarker of Chronological and Biological Ages J Gerontol A Biol Sci Med Sci (2013)
Fine structural details of glycans attached to the conserved N-glycosylation site significantly not only affect function of individual immunoglobulin G (IgG) molecules but also mediate inflammation at the systemic level. By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age. Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these three glycans can explain up to 58% of variance in chronological age, significantly more than other markers of biological age like telomere lengths. The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age. Thus, IgG glycosylation appears to be closely linked with both chronological and biological ages. Considering the important role of IgG glycans in inflammation, and because the observed changes with age promote inflammation, changes in IgG glycosylation also seem to represent a factor contributing to aging.
To create the clock, Horvath focused on methylation, a naturally occurring process that chemically alters DNA. Horvath sifted through 121 sets of data collected previously by researchers who had studied methylation in both healthy and cancerous human tissue.
Gleaning information from nearly 8,000 samples of 51 types of tissue and cells taken from throughout the body, Horvath charted how age affects DNA methylation levels from pre-birth through 101 years. To create the clock, he zeroed in on 353 markers that change with age and are present throughout the body.
Horvath tested the clock’s effectiveness by comparing a tissue’s biological age to its chronological age. When the clock repeatedly proved accurate, he was thrilled – and a little stunned.
“It’s surprising that one could develop a clock that reliably keeps time across the human anatomy,” he admitted. “My approach really compared apples and oranges, or in this case, very different parts of the body: the brain, heart, lungs, liver, kidney and cartilage.”
Aging of blood can be tracked by DNA methylation changes at just three CpG sites Genome Biology 2014
We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length.
Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.
“Dean Jones at Emory University was the first to show that human plasma GSH/GSSG is controlled at a relatively constant redox state of -137 mV in 740 healthy adults through age 50. However, an oxidative shift of about 7 mV/decade occurs over the next two decades, followed by a further decline to -110 mV in the 70 to 85-year-old group. … Other diseases associated with an oxidized plasma glutathione redox state include type 2 diabetes at -110 mV (Samiec et al., 1998) and carotid artery thickening at values more oxidized than -130 mV (Ashfaq et al., 2006)” (ref)
“In humans, an age-related oxidative shift in the ratio of reduced to oxidized glutathione, i.e. the glutathione redox status, has been demonstrated in whole blood, and peripheral blood mononuclear cells. The mean plasma cysteine/cystine redox status of human subjects shows a significant oxidative shift between the third and the ninth decade of life. This age-related oxidative shift is accompanied by a decrease in the plasma glutathione level and a decrease in the ratio of reduced versus oxidized forms of plasma albumin and other thiol/disulfide redox couples.” (ref)
Before the age of 40 years, the Eh(GSH/GSSG) value in blood plasma was kept in a stable level, the Eh(GSH/GSSG) value of 20-29 age group[(-147.3±3.4) mV]was very close to that of 30-39 years age group [(-147.2±3.0) mV], without significant difference between these two groups (P>0.05). But the Eh(GSH/GSSG) value of the other three age groups [(-141.8±3.7) mV, (-139.3±4.9) mV, (-135.9±4.4) mV, respectively] were higher than those of the 20-29 and 30-39 years age groups (P<0.05), which showed that after the age of 40 years, the Eh(GSH/GSSG) value increased with the increase of age, the older the age, the higher the Eh(GSH/GSSG) value.