Hidden secret of immortality enzyme telomeras

 

Can we stay young forever, or even recapture lost youth?

Research has recently uncovered a crucial step in the telomerase enzyme catalytic cycle. This catalytic cycle determines the ability of the human telomerase enzyme to synthesize DNA.

Research from the laboratory of Professor Julian Chen in the School of Molecular Sciences at Arizona State University recently uncovered a crucial step in the telomerase enzyme catalytic cycle. This catalytic cycle determines the ability of the human telomerase enzyme to synthesize DNA "repeats" (specific DNA segments of six nucleotides) onto chromosome ends, and so afford immortality in cells. Understanding the underlying mechanism of telomerase action offers new avenues toward effective anti-aging therapeutics. illustration depicting the enzyme telomerase This figure depicts the enzyme telomerase as well as telomeres relative to a chromosome.
Typical human cells are mortal and cannot forever renew themselves. As demonstrated by Leonard Hayflick a half-century ago, human cells have a limited replicative lifespan, with older cells reaching this limit sooner than younger cells. This "Hayflick limit" of cellular lifespan is directly related to the number of unique DNA repeats found at the ends of the genetic material-bearing chromosomes. These DNA repeats are part of the protective capping structures, termed "telomeres," which safeguard the ends of chromosomes from unwanted and unwarranted DNA rearrangements that destabilize the genome.
Each time the cell divides, the telomeric DNA shrinks and will eventually fail to secure the chromosome ends. This continuous reduction of telomere length functions as a "molecular clock" that counts down to the end of cell growth. The diminished ability for cells to grow is strongly associated with the aging process, with the reduced cell population directly contributing to weakness, illness, and organ failure.
The fountain of youth at molecular level
Counteracting the telomere shrinking process is the enzyme, telomerase, that uniquely holds the key to delaying or even reversing the cellular aging process. Telomerase offsets cellular aging by lengthening the telomeres, adding back lost DNA repeats to add time onto the molecular clock countdown, effectively extending the lifespan of the cell. Telomerase lengthens telomeres by repeatedly synthesizing very short DNA repeats of six nucleotides -- the building blocks of DNA -- with the sequence "GGTTAG" onto the chromosome ends from an RNA template located within the enzyme itself. However, the activity of the telomerase enzyme is insufficient to completely restore the lost telomeric DNA repeats, nor to stop cellular aging.
The gradual shrinking of telomeres negatively affects the replicative capacity of human adult stem cells, the cells that restore damaged tissues and/or replenish aging organs in our bodies. The activity of telomerase in adult stem cells merely slows down the countdown of the molecular clock and does not completely immortalize these cells. Therefore, adult stem cells become exhausted in aged individuals due to telomere length shortening that results in increased healing times and organ tissue degradation from inadequate cell populations.
Tapping the full potential of telomeraseUnderstanding the regulation and limitation of the telomerase enzyme holds the promise of reversing telomere shortening and cellular aging with the potential to extend human lifespan and improve the health and wellness of elderly individuals. Research from the laboratory of Chen and his colleagues, Yinnan Chen, Joshua Podlevsky and Dhenugen Logeswaran, recently uncovered a crucial step in the telomerase catalytic cycle that limits the ability of telomerase to synthesize telomeric DNA repeats onto chromosome ends.
"Telomerase has a built-in braking system to ensure precise synthesis of correct telomeric DNA repeats. This safe-guarding brake, however, also limits the overall activity of the telomerase enzyme," said Professor Chen. "Finding a way to properly release the brakes on the telomerase enzyme has the potential to restore the lost telomere length of adult stem cells and to even reverse cellular aging itself."
This intrinsic brake of telomerase refers to a pause signal, encoded within the RNA template of telomerase itself, for the enzyme to stop DNA synthesis at the end of the sequence 'GGTTAG'. When telomerase restarts DNA synthesis for the next DNA repeat, this pause signal is still active and limits DNA synthesis. Moreover, the revelation of the braking system finally solves the decades-old mystery of why a single, specific nucleotide stimulates telomerase activity. By specifically targeting the pause signal that prevents restarting DNA repeat synthesis, telomerase enzymatic function can be supercharged to better stave off telomere length reduction, with the potential to rejuvenate aging human adult stem cells.
Human diseases that include dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis have been genetically linked to mutations that negatively affect telomerase activity and/or accelerate the loss of telomere length. This accelerated telomere shortening closely resembles premature aging with increased organ deterioration and a shortened patient lifespan from critically insufficient cell populations. Increasing telomerase activity is the seemingly most promising means of treating these diseases.
While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. Augmenting and regulating telomerase function will have to be performed with precision, walking a narrow line between cell rejuvenation and a heightened risk for cancer development.
Distinct from human stem cells, somatic cells constitute the vast majority of the cells in the human body and lack telomerase activity. The telomerase deficiency of human somatic cells reduces the risk of cancer development, as telomerase fuels uncontrolled cancer cell growth. Therefore, drugs that increase telomerase activity indiscriminately in all cell types are not desired. Toward the goal of precisely augmenting telomerase activity selectively within adult stem cells, this discovery reveals the crucial step in telomerase catalytic cycle as an important new drug target. Small molecule drugs can be screened or designed to increase telomerase activity exclusively within stem cells for disease treatment as well as anti-aging therapies without increasing the risk of cancer.

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Soil cannot halt climate change

 

Long-term field experiments, dating back as far as 1843, demonstrate that modern carbon emissions cannot be locked in the ground to halt global warming

Unique soils data from long-term experiments, stretching back to the middle of the nineteenth century, confirm the practical implausibility of burying carbon in the ground to halt climate change. The idea of using crops to collect more atmospheric carbon and locking it into soil organic matter to offset fossil fuel emissions was launched at COP21, the 21st annual Conference of Parties to review the United Nations Framework Convention on Climate Change in Paris in 2015.

Unique soils data from long-term experiments, stretching back to the middle of the nineteenth century, confirm the practical implausibility of burying carbon in the ground to halt climate change, an option once heralded as a breakthrough.

The findings come from an analysis of the rates of change of carbon in soil by scientists at Rothamsted Research where samples have been collected from fields since 1843. They are published today in Global Change Biology.

The idea of using crops to collect more atmospheric carbon and locking it into soil's organic matter to offset fossil fuel emissions was launched at COP21, the 21st annual Conference of Parties to review the United Nations Framework Convention on Climate Change in Paris in 2015.

The aim was to increase carbon sequestration by "four parts per 1000 (4P1000)" per year for 20 years. "The initiative was generally welcomed as laudable," says David Powlson, a soils specialist and Lawes Trust Senior Fellow at Rothamsted.

"Any contribution to climate change mitigation is to be welcomed and, perhaps more significantly, any increases in soil organic carbon will improve the quality and functioning of soil," he adds. "The initiative has been adopted by many governments, including the UK."

But there have been serious criticisms of the initiative. Many scientists argue that this rate of soil carbon sequestration is unrealistic over large areas of the planet, notes Powlson: "Also, increases in soil carbon do not continue indefinitely: they move towards a new equilibrium value and then cease."

The Rothamsted scientists used data from 16 experiments on three different soil types, giving over 110 treatment comparisons. "The results showed that the "4 per 1000" rate of increase in soil carbon can be achieved in some cases but usually only with extreme measures that would mainly be impractical or unacceptable," says Paul Poulton, lead author and an emeritus soils specialist.

"For example, large annual applications of animal manure led to increases in soil carbon that continued over many years but the amounts of manure required far exceeded acceptable limits under EU regulations and would cause massive nitrate pollution," notes Poulton.

Removing land from agriculture led to large rates of soil carbon increase in the Rothamsted experiments but doing this over large areas would be highly damaging to global food security, record the researchers.

Similarly, they add, returning crop residues to soil was effective at increasing carbon sequestration but, in some countries, this is already done so cannot be regarded as a totally new practice.

"For example, in the UK about 50% of cereal straw is currently returned to soil and much of the remainder is used for animal feed or bedding, at least some of which is later returned to soil as manure," says Poulton. "In many other countries, however, crop residues are often used as a source of fuel for cooking."

Moving from continuous arable cropping to a long-term rotation of arable crops interspersed with pasture led to significant soil carbon increases, but only where there was at least 3 years of pasture in every 5 or 6 years, record the researchers.

"Although there can be environmental benefits from such a system, most farmers find that it is uneconomic under present circumstances," says Powlson. "To make this change on a large scale would require policy decisions regarding changes to subsidy and farm support. Such a change would also have impacts on total food production."

The authors of this study conclude that promoting the "4 per 1000" initiative as a major contribution to climate change mitigation is unrealistic and potentially misleading.

They suggest that a more logical rationale for promoting practices that increase soil organic carbon is the urgent need to preserve and improve the functioning of soils, both for sustainable food security and wider ecosystem services.

For climate change mitigation through changes in agricultural practices, they point out that measures to decrease emission of nitrous oxide, a greenhouse gas almost 300 times more powerful than carbon dioxide, may be more effective.

 

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The moon formed inside a vaporized Earth synestia

 

A new explanation for the Moon origin has it forming inside the Earth when our planet was a seething, spinning cloud of vaporized rock, called a synestia. The new model resolves several problems in lunar formation.

A new explanation for the Moon origin has it forming inside the Earth when our planet was a seething, spinning cloud of vaporized rock, called a synestia. The new model led by researchers at the University of California, Davis and Harvard University resolves several problems in lunar formation and is published Feb. 28 in theJournal of Geophysical Research -- Planets

"The new work explains features of the Moon that are hard to resolve with current ideas," said Sarah Stewart, professor of Earth and Planetary Sciences at UC Davis. "The Moon is chemically almost the same as the Earth, but with some differences," she said. "This is the first model that can match the pattern of the Moon composition."
Current models of lunar formation suggest that the Moon formed as a result of a glancing blow between the early Earth and a Mars-size body, commonly called Theia. According to the model, the collision between Earth and Theia threw molten rock and metal into orbit that collided together to make the Moon.
The new theory relies instead on a synestia, a new type of planetary object proposed by Stewart and Simon Lock, graduate student at Harvard and visiting student at UC Davis, in 2017. A synestia forms when a collision between planet-sized objects results in a rapidly spinning mass of molten and vaporized rock with part of the body in orbit around itself. The whole object puffs out into a giant donut of vaporized rock.

Synestias likely don't last long -- perhaps only hundreds of years. They shrink rapidly as they radiate heat, causing rock vapor to condense into liquid, finally collapsing into a molten planet.
"Our model starts with a collision that forms a synestia," Lock said. "The Moon forms inside the vaporized Earth at temperatures of four to six thousand degrees Fahrenheit and pressures of tens of atmospheres."
An advantage of the new model, Lock said, is that there are multiple ways to form a suitable synestia -- it doesn't have to rely on a collision with the right sized object happening in exactly the right way.
Once the Earth-synestia formed, chunks of molten rock injected into orbit during the impact formed the seed for the Moon. Vaporized silicate rock condensed at the surface of the synestia and rained onto the proto-Moon, while the Earth-synestia itself gradually shrank. Eventually, the Moon would have emerged from the clouds of the synestia trailing its own atmosphere of rock vapor. The Moon inherited its composition from the Earth, but because it formed at high temperatures it lost the easily vaporized elements, explaining the Moon's distinct composition.
Additional authors on the paper are Michail Petaev and Stein Jacobsen at Harvard University, Zoe Leinhardt and Mia Mace at the University of Bristol, England and Matija Cuk, SETI Institute, Mountain View, Calif. The work was supported by grants from NASA, the U.S. Department of Energy and the UK's Natural Environment Research Council.

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