Three Years You May Want to Hibernate

Years 34, 60, and 78: When Bad Things Happen

Scientists working at Stanford University, Albert Einstein College of Medicine, and institutions in Germany and Italy, have determined that protein markers for human ageing change significantly during three years of a person’s life on average — age 34, age 60, and age 78. They detected these critical “shift points” by a close analysis of body proteins from over four thousand adult subjects ranging from age 18 to age 95. Out of almost 3,000 proteins tested, over 1,000 proteins varied in concentration with age. On average, significant shifts in levels of these “tell-tale” proteins occurred at the three ages mentioned — 34, 60, and 78.

We measured 2,925 plasma proteins from 4,331 young adults to nonagenarians and developed a novel bioinformatics approach which uncovered profound non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways, and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways of aging and disease and offers potential pathways for aging interventions.

… To determine whether the plasma proteome can predict chronological age and serve as a “proteomic clock,” we used 2,858 randomly selected subjects to fine-tune a predictive model that was tested on the remaining 1,473 subjects (Fig. 1f). We identified a sex-independent plasma proteomic clock consisting of 373 proteins (Supplementary Table 7). This clock was highly accurate in predicting chronological age in the discovery, validation and 4 small independent cohorts (r=0.93-0.97, Fig. 1g and Supplementary Fig. 3a-b).

Remarkably, subjects that were predicted younger than their chronologic age based on their plasma proteome performed better on cognitive and physical tests (Fig. 1h and Supplementary Table 8). While a reduced model comprising only 9 proteins predicted age with good accuracy (Supplementary Fig.3c and Supplementary Table 7), a combination of different sets of proteins may be required to model changes in a large set of clinical and functional parameters (Supplementary Fig.3d). __ Study in Nature

Monitoring a person’s total body proteins (proteome) would seem to provide a measure of “functional ageing.” By pointing out particular proteins that are causing significant problems, proteomic monitoring may also suggest potentially useful treatments.

Hormones Change with Ageing Too

We have known for a long time that different endocrine hormones change in blood concentration with ageing. Thymosin, DHEA, melatonin, estrogen, testosterone, growth hormone, and other hormones decrease after puberty and young adulthood. The thymus gland is the earliest endocrine gland to shrivel away, usually soon after puberty.

A recent small research study (the TRIIM trial) tested the effects of hormone replacement therapy with HGH, DHEA, and the diabetes drug metformin in males between 51 and 65 years of age, to see whether the thymus gland could be rejuvenated — thus improving immune regulation.

In the TRIIM trial, the scientists took blood samples from participants during the treatment period. Tests showed that blood-cell count was rejuvenated in each of the participants. The researchers also used magnetic resonance imaging (MRI) to determine the composition of the thymus at the start and end of the study. They found that in seven participants, accumulated fat had been replaced with regenerated thymus tissue.
Rewinding the clock

Checking the effect of the drugs on the participants’ epigenetic clocks was an afterthought. The clinical study had finished when Fahy approached Horvath to conduct an analysis.

Horvath used four different epigenetic clocks to assess each patient’s biological age, and he found significant reversal for each trial participant in all of the tests. “This told me that the biological effect of the treatment was robust,” he says. What’s more, the effect persisted in the six participants who provided a final blood sample six months after stopping the trial, he says. __ https://www.nature.com/articles/d41586-019-02638-w

Study abstract

This suggests that hormone replacement therapy can potentially reverse some of the effects of “natural ageing.”

Chromosomes Change with Age

The male “Y” chromosome is often lost as men age, in certain tissues. This chromosome loss is associated with increased morbidity from different diseases, including cancers and heart disease.

Now a new study—the largest yet of this phenomenon—estimates that 20 percent of 205,011 men in a large genetic database called the UK Biobank have lost Y chromosomes from some detectable proportion of their blood. By age 70, 43.6 percent of men had the same issue. It’s unclear exactly why, but the authors think these losses might be the most glaring sign of something else going wrong inside the bodies of these men: They are allowing mutations of all kinds to accumulate, and these other mutations could be the underlying links to cancer and heart disease.

Mutations are, after all, spontaneously popping up in the human body all the time. Every cell division produces errors as small as miscopying one letter or as large as losing an entire chromosome. So over a lifetime, this can lead to what scientists call “clonal mosaicism”—in which a person’s body is a mosaic of distinct populations of cells, each with their accumulated mutations. This is true of everyone to some extent, but it becomes more relevant as you get older. “The more you age, the more errors have taken place in cell division,” says John R. B. Perry, a biologist at the University of Cambridge who led the recent study. __ https://www.theatlantic.com/science/archive/2019/12/men-lose-y-chromosomes-cells-they-age/603013/

Note the jump in number of men with missing Y chromosomes around the age of 70. Something is happening over time to cause proteins to change, hormones to decrease, and entire chromosomes to disappear. (In some women, an X chromosome is lost with age, in certain tissues.)

More on the study on proteome changes with ageing:

“We’ve known for a long time that measuring certain proteins in the blood can give you information about a person’s health status – lipoproteins for cardiovascular health, for example,” says neurologist Tony Wyss-Coray, from the Stanford Alzheimer’s Disease Research Center (ADRC).

“But it hasn’t been appreciated that so many different proteins’ levels – roughly a third of all the ones we looked at – change markedly with advancing age.”

The researchers were able to set up a system whereby the mix of 373 selected proteins in the blood could be used to accurately predict someone’s age, within around three years or so.

Interestingly, when the system failed by predicting an age that was too young, the subject was usually very healthy for their age.

Another finding from the study gives more evidence to something that’s been long suspected: men and women age differently. Of the 1,379 proteins that were found to change with age, 895 (nearly two-thirds) were significantly more predictive for one sex compared with the other.

These are still early findings – the researchers say any clinical applications could still be 5-10 years off – and it’s going to take a lot more work to figure out how all of these proteins are markers for ageing, and whether or not they actually contribute to it. __ https://www.sciencealert.com/our-bodies-age-in-three-separate-shifts-according-new-blood-tests

Ageing and Inflammation

Inflammation contributes to ageing in virtually all organs and tissues. Unfortunately, chronic inflammation tends to accompany ageing in almost everyone. Once the cycle of inflammatory decline begins, it tends to feed itself in a positive feedback manner — but at various rates depending upon the person.

Many proteins of inflammation occur in the body, and changing levels of such proteins are likely to be used as biomarkers of ageing in the future.

There are several possible factors that initiate and maintain a low-grade inflammatory response. These include aging, unbalanced diet, low level of sex hormones, and smoking. In contrast to young individuals, aged individuals have consistently elevated levels of inflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (2), which may induce muscle atrophy and cancer through DNA damage. Visceral fat tissue from obese individuals can also produce both IL-6 and TNF-α, affecting systemic metabolism (3, 4). The accumulation of macrophages in visceral fat seems to be proportional to body mass index and appears to be a major source of low-grade persistent, systemic inflammation and insulin resistance in obese individuals (5, 6). __ Frontiers in Cardiovascular Medicine 22 Feb 2018 via Fight Aging

Anti-inflammatory substances — such as curcumin — are thought to reduce risk for degenerative diseases such as Alzheimer’s Disease.

On Average, Men Die Younger than Women

We are finding clues to why men live shorter lives on average than women. The proteome study above provides some clues. Research on the loss of the Y chromosome also suggests reasons for the discrepancy. Differences in changing levels of endocrine hormones may also provide clues.

Unlike feminists, men do not want to level the playing field by making the opposite sex die younger. Strangely enough, most men would prefer for everyone to live longer and more satisfying lives.

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