- 1 Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.
- 2 Loving-Kindness Meditation practice associated with longer telomeres in women.
According to the Hayflick limit, most of our cells divide from 50 to 70 times. With each division, the telomeres shorten. 70 population doublings equates to approximately 120 years of life. Progenitor cells (also called stem cells) and differentiated cells are thus limited to Hayflick’s limit of 70 population doublings. Although adult-derived stem cells, (i.e., totipotent stem cells, pluripotent stem cells, germ layer lineage stem cells, ectodermal stem cells, mesodermal stem cells, and endodermal stem cells) contain the telomerase enzyme, these cells are still subject to the laws of entropy, notwithstanding their unlimited cancer-like proliferation potential. On the other hand, telomerase activators might repair or extend the telomeres of healthy cells, thus extending their Hayflick limit. Telomerase activation might also lengthen the telomeres of immune system cells enough to prevent cancerous cells from developing from cells with very short telomeres. (8)
According to Hayflicks, 99 percent of human existence, the average longevity has been 18 years old. today, in developed countries, more than 80% of the population today will survive past the age of 70. About 150 years ago, only 20% did.
The natural laws of physics may dictate that most things must die. But that does not mean we cannot use nature’s templates to extend healthy human lifespan beyond 120 years.
Telomeres are the protective caps on the ends of the strands of DNA called chromosomes, which house our genomes. In young humans, telomeres are about 8,000-10,000 nucleotides long. They shorten with each cell division, however, and when they reach a critical length the cell stops dividing or dies. This internal “clock” makes it difficult to keep most cells growing in a laboratory for more than a few cell doublings.
‘Turning back the internal clock’
“Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life,” said Helen Blau, PhD, professor of microbiology and immunology at Stanford and director of the university’s Baxter Laboratory for Stem Cell Biology. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”
A paper describing the research was published today in the FASEB Journal. Blau, who also holds the Donald E. and Delia B. Baxter Professorship, is the senior author. Postdoctoral scholar John Ramunas, PhD, of Stanford shares lead authorship with Eduard Yakubov, PhD, of the Houston Methodist Research Institute.
Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.
Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.
In contrast to laboratory mice, the length of killifish telomeres, which average around 6,000-8,000 nucleotides, is similar to that of humans. As a result, Harel and his colleagues were able to quickly see the effect of a telomerase-disabling mutation in the fish. Interestingly, fish in which telomerase activity was disabled displayed a variety of traits that are similar to those seen in humans with a disorder called dyskeratosis congenita, which is also due to a mutation in telomerase.
“Very quickly we began to see an effect on rapidly dividing tissues such as the blood, gut and sperm,” said Harel. “The fish rapidly become sterile, their intestines began to atrophy and they made fewer types of blood cells than their peers.”
The researchers conclude that the killifish is currently the fastest way to study diseases of telomere shortening in vertebrates. They are hopeful that the other mutant strains will be equally useful in their lab and in other labs worldwide.
“Itamar has generated a range of tools necessary to study how genetic changes affect physical characteristics of the killifish,” said Brunet. “It’s a true ‘genotype to phenotype’ platform, and is likely to be transformative. Now we have what is essentially a high-throughput vertebrate model for aging research.”
Loving-Kindness Meditation practice associated with longer telomeres in women.
Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p=.083); among women, the LKM practitioners had significantly longer RTL than controls, (p=.007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity.
The French Mediterranean Jeanne Calment lived to 122.6 years. She was in great shape until 120. thereafter, after a fall, she slowly deteriorated, but always kept her wit until the last second. She confirmed what Happiness Medicine Institute teaches, that one of the secrets to a healthy life span is happiness via laughter and an attitude of unflappability..
Bottom more bland one
How long can human beings live? Is there an outside limit? Do we know enough about aging to break through possible biological barriers? Is the current approach to curing “age associated diseases” like Alzheimer’s flawed? Experts are sharply divided.
In 1962 eminent biologist Leonard Hayflick discovered that normal human fetal cells replicate a limited number of times. This phenomenon promptly acquired the moniker the “Hayflick Limit.” Later, biologists Calvin Harley and Carol Greider provided the molecular explanation for the Hayflick limit with their discovery that telomeres, the DNA biological material in every cell of our bodies, diminish each time cells divide.
In contrast, cancer cells, which are immortal, produce an enzyme called telomerase that maintains the length of telomeres and enables cancer cells to replicate without limit. The strategy of extending the life of normal cells by injecting telomerase has proven thorny, as reported by Dr. Elizabeth Blackburn, co-discoverer of telomerase: “too much telomerase can help confer immortality onto cancer cells and actually increase the likelihood of cancer, whereas too little telomerase can also increase cancer by depleting the healthy regenerative potential of the body..telomerase shots are not the magical anti-aging potion….”
The finite capacity of normal human fetal cells to divide (on average about 50 times) suggested to Hayflick that aging is responsible for the end of normal cell replication and eventually death. Other researchers translated Hayflick’s findings into a maximum human lifespan of 120 years.
A 2016 study at the Albert Einstein School of Medicine came up with a similar human lifespan limit of 115 years. The investigators drew their conclusion from surveys of longevity and mortality records in more than forty countries since 1900. While their findings showed an impressive increase in the number of people living beyond age 100 in recent decades, rarely did centenarians live longer than 115 years. One exception, Frenchwoman Jeanne Calment, died at age 122. She was a media sensation because she exceeded the traditional limit for longevity.
The dramatic increase in life expectancy from 18 years (at birth) in prehistoric times to an average of 79 in the U.S. today (and 1-4 years longer in more than 25 other countries) is not due to breakthroughs in our understanding of the biology of aging. Rather, it’s been achieved through the reduction in infant mortality, public health measures such as clean water, improved sanitation, better nutrition, healthy life styles, and the remarkable boost when antibiotics and vaccines were introduced.
But is the Hayflick Limit fixed, or is it a biological barrier that can be penetrated? Opinions vary.
At one extreme, Cambridge University trained Dr. Aubrey de Grey, Chief Science Officer of the SENS Research Foundation for the study of aging claims that emerging breakthroughs in the biology of aging have brought human lifespan to the verge of vastly extended longevity—and perhaps immortality. The first person to live to 1,000 years is likely walking the earth right now, he declares.
I met Aubrey de Grey several years ago at a screening of the film To Age or Not To Age, sponsored by the International Longevity Center. He was one of the researchers featured in the documentary. Afterwards I approached him with a question.
“Do you think civilization is ready for immortality?” I asked, since immortality has obvious implications for the social, economic, and political functioning of society.
De Grey didn’t like my question. He immediately launched into a lengthy rant. “Do you know how many people die each day and that it’s not necessary,” he remarked. “We have the means and knowledge…” I quickly realized that de Grey champions another version of right to life. So sure is he that death is not inevitable that he recoils at the idea that we dare think otherwise.
Dr. Leonard Hayflick takes a strong stand against De Grey’s position on life extension. And he has little respect for those touting “cures for aging.” The “fountain of youth” business, he says, is the first or second oldest profession.
What does Hayflick think of the work of MIT biologist Dr. Leonard Guarente I wanted to know. In 2016 Guarente generated a lot of fanfare when his newly formed company, Elysium, introduced a nutritional supplement called Basis. The main ingredient of Basis, nicotinamide riboside (NR), raises the body’s levels of nicotinamide adenine dinucleotide (NAD), which in turn, Guarente claims, can slow the aging process by boosting mitochondria, the energy dynamo of cells that diminishes with age. While Guarente’s Basis and anti-aging products of other companies may improve some aspects of bodily functioning, do they put the brakes on aging? Hayflick is doubtful if not dismissive of that notion.
I interviewed Dr. Hayflick on the telephone on October 27th and 29th 2016. He spoke from his home in Northern California. The strength of his voice, not to mention his convictions, belie his eighty-eight years. And he anticipates many productive years ahead, based on the principle that the best way to insure longevity is to pick your parents carefully. His mother lived to 106.
While he agrees that biology plays a role in longevity, Hayflick rejects claims that a genetic aging code is about to be broken, thus opening the floodgates for unlimited lifespans. In stark contrast to those who argue that researchers have accumulated a trove of knowledge about aging, Hayflick insists that “We know very little if not zero about the fundamental cause of aging.”
He emphasizes that all the advances in average life expectancy that have been derived from prevention and cures for diseases have not told us anything about the fundamental etiology of aging. “We do not know why cells age,” Hayflick told me. And until we expand our knowledge of the fundamental cause of aging he does not foresee significantly extending average life expectancy; he is even less hopeful about extending human lifespan beyond the current limit.
Hayflick says that if cures are miraculously found for the leading causes of death, that will add about 13 years to average life expectancy. But, he points out, those cures will not increase the lifespan beyond the current limit. He warns: “People will continue to die as a result of aging.” The explanation for why they are dying, he insists, will only be found by unraveling the mystery of the cause of molecular and cellular aging.
“How likely is that to happen?” I asked him. “Very unlikely,” he admitted. Hayflick laments that two to three percent at most of the $1.27 billion that the National Institute of Aging (NIA) spends annually on aging research is allocated to fundamental biological research. That’s why “little work is being done on the basic understanding of aging—not only in this country but worldwide.”
According to Transparency Market Research, the anti-aging market is projected to reach $91.7 billion globally by 2019. Most of that money will be for anti-aging products and services with possibly only a tiny percentage for basic biological research.
Dr. Jan Vijg, Chair in Molecular Genetics at the Albert Einstein School of Medicine in New York City, and a lead researcher on the recent longevity study, confirmed in an interview on November 16, 2016, that a miniscule amount of funding goes to basic biological research, where many of the questions about aging are more likely to find answers. Vijg agrees with Hayflick about the dearth of knowledge about cellular aging. He says we know a lot about factors such as genomes (the DNA of genes) that affect cellular senescence but the question of why cells age remains largely unanswered.
On the positive side, Vijg notes that scientists in the field of aging are increasingly focusing on the biology of aging, not just the cure of diseases. He told me that he has recently applied for a large grant for the study of drugs that target aging rather than specific diseases. Hayflick, he acknowledges, “was the original defender of this position to study aging per se and now he’s been proven correct.”
If that direction is endorsed by a growing consensus of scientists, why the dearth of funding, I asked?
Dr. Vijg points to an entrenched establishment driven by the public, special interests, and lobbyists who want immediate results. People accept aging and death as natural facts of life, Vijg says, but they don’t accept diseases as natural and thus they want cures for them. Basic research may seem abstract and remote. Few laypeople grasp that unraveling the underlying biology of aging could produce faster and more successful results.
Token funding for basic research on the biology of aging makes no sense, Hayflick argues, when it’s clear that aging is the condition that increases vulnerability to age-associated diseases. Physicians and other experts on aging talk glibly, he says, about age-associated diseases such as cancer, cardiovascular, Alzheimer’s, and other illnesses for which the elderly are at greater risk. And then they immediately utter the mantra that the greatest risk factor for age-associated diseases is aging. “But,” he adds, “they never ask themselves why all these major causes of death are occurring in older people.” If you try to answer that question logically, he continues, “you come to the conclusion that there must be something in old cells that provides the milieu or the opportunity for age-associated diseases that does not occur in young cells.” Isn’t it therefore highly probable, he conjectures, that “old cells may provide the condition that allows for the emergence of all age-associated diseases?”
If Hayflick’s analysis is correct, shouldn’t a significant part of the fifty percent of the NIA budget for aging research, which Hayflick says is designated for the treatment and cure of Alzheimer’s (Vijg estimates an even higher percentage), be shifted to research on molecular and cellular aging, where a cure may be found?
Hayflick gets emotional in his frustration that researchers are not aggressively pursuing a strategy to understand why old cells are different from young cells: “Why in the hell aren’t we studying the fundamental biology of aging if that is the major risk factor for age-associated diseases? Why are we ignoring it almost 100 percent?”
While unlocking the keys to cellular aging might enable vast numbers of people to live closer to the limit of life expectancy, Hayflick still cautions that it will not extend lifespan beyond its current limit. What then does he say about the limit? Is it fixed or can it be extended. And if it is possible to increase it, by how much?
Here Hayflick’s analysis turns to an overarching law of nature. He explains that cells, like all things animate and inanimate, are subject to the second law of thermodynamics, which states that energy dissipates or spreads out when not constrained. Applied to aging, this means that entropy (energy dissipation) increases over time—and the increase in entropy forecasts the inevitability of death. Sounds pessimistic, but is that the end of the story? Maybe not.
Vijg acknowledges entropy as a limiting factor, but he believes it could be slowed if we had a better understanding of entropy at the cellular level. He also expresses great faith in science and therefore will not rule out future discoveries that could lead to a significant increase in human lifespan. Hayflick as well will not bet against science, but he adds this stern caveat: “First we must invest substantially in the study of the basic biology of aging.”
Note: The first and second laws of thermodynamics were introduced by Rudolf Clausius and William Thomson around 1850.