Nature of End of Life Death Spiral Revealed

Nature of End of Life Death SpiralRevealed

The devil continues to be in thedetails and this is early days in terms of understanding natural death.  Here we are seeing our understanding somewhatimprove, at least in terms of what is happening to telomeres.

The take home so far is thatfailing telomeres trigger changes elsewhere that lead to a swift decline thatcoincides very well with observation. The arbitrary nature of cell changes lead to the suspicion that lifeextension on the cellular basis may very well be a practical option availableto us.

One needs to answer the question ofwhy now?

Harvard finds the core pathway of aging is malfunctioning telomeres

FEBRUARY 14, 2011
Scientists at the Harvard-affiliated Dana-Farber Cancer Institutesay they have identified the root molecular cause of a variety of ills broughton by advanced age, including waning energy, failure of the heart and otherorgans, and metabolic disorders such as diabetes. The scientists foundthat the basic cause of age-related health declineis malfunctioning telomeres — the end caps on cells’ chromosomes that protectthem against DNA damage. As cells reach their predetermined limit of times thatthey can divide, the telomeres become shortened and frayed, making thechromosomal ends vulnerable to increased rates of unrepaired DNA damage.

UPDATE Aubrey de Grey (of SENS) opinion - It's not a very important paper.The presence of short telomeres makes cells unhappy, and they respond bychanging their behaviour in various ways, including depression ofmitochondrial activity. That tells us nothing at all about what happens in theabsence of short telomeres, which is what we need to know for normal aging.

NBF analogy based on Aubrey comment - having no oil in your car causes parts towear out faster but just maintaining oil levels is not sufficient to keep yourcar running for hundreds of years.

Telomere dysfunction activates p53-mediated cellular growth arrest,senescence and apoptosis to drive progressive atrophy andfunctional decline in high-turnover tissues. The broader adverse impact oftelomere dysfunction across many tissues including more quiescent systemsprompted transcriptomic network analyses to identify common mechanismsoperative in haematopoietic stem cells,heart and liver. These unbiased studies revealed profound repression ofperoxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta(PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and thedownstream network in mice null for either telomerase reverse transcriptase(Tert) or telomerase RNA component (Terc) genes.Consistent with PGCs as master regulators of mitochondrial physiology andmetabolism, telomere dysfunction is associated with impaired mitochondrialbiogenesis and function, decreased gluconeogenesis, cardiomyopathy,and increased reactive oxygen species. In the setting of telomere dysfunction,enforced Tert or PGC-1α expression or germline deletion of p53 (also known asTrp53) substantially restores PGC network expression, mitochondrial respiration,cardiac function and gluconeogenesis. We demonstrate that telomere dysfunctionactivates p53 which in turn binds and represses PGC-1α and PGC-1β promoters,thereby forging a direct link between telomere and mitochondrial biology. Wepropose that this telomere–p53–PGC axis contributes to organ and metabolicfailure and to diminishing organismal fitness in the setting of telomeredysfunction

Faced with this increasing reservoir of injured DNA, cells activate agene, p53, that sounds an alarm and shuts down the cells’ normal growth anddivision cycle, ordering them to rest until the damage can be repaired or, ifnot, to self-destruct.

Scientists previously had blamed this emergency shutdown and cell death forage-related deterioration of organs whose cells divide rapidly and arerejuvenated by reserves of adult stem cells. Such tissues include skin,intestinal lining, and blood cells, among others, which generate trillions ofnew cells each day of life.

However, left unanswered is how cells with less cell division, such as theheart or the liver, sustain equivalent levels of aging. The scientists felt ifthey could solve this mystery, they might gain new insights into how DNA damagecould lead to age-related decline across all organs.

The new findings demonstrate that the telomere dysfunction and activation ofp53 also trigger a wave of cellular and tissue degeneration that linkstelomeres to well-known mechanisms of aging that are not simply related torapid growth and division. In other words, telomere dysfunction is not justone culprit in the declining health of advanced age. It’s the kingpin,according to DePinho and his colleagues.

DePinho published a study in Nature in January 2011 that demonstrated it waspossible to reverse the symptoms of extreme aging in mice by increasing theirlevels of telomerase, the enzyme that maintains the health of the telomeres.

In this new, larger role, the telomere dysfunction also sets off an array ofreactions leading to diminished health and longevity. For example, musclessuffer a loss of mitochondria, a cell’s chemical power plant, causing waningvitality and failure of the heart and other organs. Risks of metabolicdisorders such as diabetes are increased.

In addition, the process weakens the body’s antioxidant defenses against thedamaging molecules known as reactive oxygen species, or “free radicals,” thataccumulate with age and exposure to stress. Until now, some researchers hadlabeled the decline in mitochondria or the buildup of free radicals as theprimary causes of age-related ills.
The new work integrates these seemingly disparate mechanisms intoone unified theory of aging.

Telomere dysfunction causes this wave of metabolic and organ failure, thescientists found, because when the p53 gene is activated, it represses thefunctions of two master regulators of metabolism, PGC1-alpha and PGC1-beta.This dialing down of the regulators diminishes metabolic processes needed toprovide energy and resist stress. In the mouse experiments, the scientistsshowed that “knocking out” p53 in mice released the brakes on PGC1-alpha andPGC1-beta.

“This is the first study that directly links telomere dysfunction to regulatorsof the mitochondria and antioxidant defense via p53,” DePinho said. “Thediscovery of this new pathway of aging integrates a lot of different ideaspeople have had and gives us a better understanding of the aging process.”

By unifying several major pathways of aging under the umbrella of telomeredysfunction, he said, the findings may yield new targets for therapies. Thediscoveries also may underlie the relatively sudden and rapid failure of thebody leading to the end of life.

Because telomere dysfunction weakens defenses against damage by freeradicals, or reactive oxygen species,” DePinho said, “we think this exposestelomeres to an accelerated rate of damage which cannot be repaired and therebyresults in even more organ deterioration. In effect, it sets in motion a deathspiral.”

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