Preliminary Longevity & Mind Enhancement Meditation Exercise
“And the LORD said, My spirit shall not always strive with man, for that he also is flesh: yet his days shall be one hundred and twenty years.” (Genesis 6:3: King James Version)
Researchers at the University of California were the first to show that meditators have significantly higher telomerase activity than non-meditators. More supporting published evidence from the Workshop’s presentation will later corroborate this piece of assertion. Furthermore, the regular practice of specific types of Meditations will simultaneiously signal longevity genes to activate telomerase and sharpen both intuition and focus. As a bonus, intellectual assimilation of the content of this Workshop will be enhanced. We will therefore begin this 8 hours workshop with a guided Meditation practice of 20 minutes or so.
The Magic of Meditation: From Genomic Expression to JDV Consciousness Activation
In 2011, researchers at Harvard were among the first to demonstrate that just eight weeks of mindfulness meditation training caused significant increase in the thickness of the hippocampus, one of the key brain organs. (Source) In this perspective, the same team of Harvard researchers also found that mindfulness meditation decreases brain cell volume in the amygdala, the part of our brain responsible for fear, anxiety and stress. (Source) These changes matched with the participants’ self-reports of their stress levels, demonstrating how changes in the brain correlate with subjective perception and feelings as well. Since focusing our attention on an object (ex: breath or mantra) is one of the central practices of meditation, it’s no surprise that meditation should help improve our ability to focus and be less susceptible to distractions. (Source) Improved concentration and attention is one of the most well-studied benefits of meditation. This is why it makes sense to start off this Workshop with some mind-blowing meditation which we will teach you.
Introduction to Holistic Rejuvenation Medicine
“The field of ageing research has been completely transformed in the past decade. . . . When single genes are changed, animals that should be old stay young. In humans, these mutants would be analogous to a ninety year old who looks and feels forty-five. On this basis we begin to think of ageing as a disease that can be cured, or at least postponed. . . . The field of ageing is beginning to explode, because so many are so excited about the prospect of searching for – and finding – the causes of ageing, and maybe even the fountain of youth itself”. (Guarente and Kenyon, Nature, 2000)
For millennia, the aging process has been considered to be uncontrollable, even when the average lifespan did not surpass 40 years, which was just a little over 100 years ago. That changed with Professor Elizabeth Blackburn’s discovery of the telomerase gene. (Source) Furthermore, in the early nineties, research on C. elegans, (a tiny nematode worm) confirmed that a single gene mutation extended its life, and that another mutation blocked that extension. (Source) The idea that age could be tweaked by twiddling a few control genetic switches ignited a research and investment boom. As more geroscientists got better motivated to attempt to break and hack the Longevity Code, new findings started to reveal key biological clocks that epigenically switched on and off longevity genes.
In this perspective, various clinical interventions did increase the worm’s lifespan by a factor of ten and those of lab mice by a factor of two. (Source) Thereafter, telomeres of skin cells were tweaked to lengthen considerably, thanks to a new Lab procedure fine-tuned by Stanford university School of Medicine scientists, these cells were able to divide up to 40 more times more than untreated cells, which means that human somatic cells have been shown to surpass the Hayflick limit and potentially extend their lifespan 40 times more than before. “Skin cells with telomeres lengthened by the procedure were able to divide up to 40 more times than untreated cells”. (Source)
The scientific consensus thus transformed. Aging went from being a God given blessing or Satan’s curse, to an inevitable final stage (Cf Time cover from 1958: “Growing Old Usefully”), followed by a social issue (Time, 1970: “Growing Old in America: The Unwanted Generation”) to this avoidable “je ne sais quoi” phenomenon (1996: “Forever Young”) that could defer death to 142 years for starts (Cf 2015: Time “This Baby Could Live to Be 142 Years Old”).
However, the excitement was not long lasting, if only because it was discovered not too long ago that telomerase was not the central longevity engine. The Longevity Code cook-book is far more complex for mammals and even more so for humans than for a C. Elegans worm, fly, mouse or even the bat (who has an exceptionally long lifespan). Hence, the presentor’s scientific attitude is to prefer the known fundamentals that work to at least 122 years of age while being open to and expecting the best of bio-tech longevity engineering stratagems, many of which are still in the early phases of clinical trials and concomitant marketing schemes.
As we will see, notwithstanding the total and irresponsible lack of drug-supplement interactions, there are many dozens of ongoing drugs and supplements that are already being used in today’s anti-aging and baby-boomer communities, from telomerase activators and senescent cell removal, (senolytics) to autophagy inducers, caloric restriction mimickers, blood donor plasma transfer, nano-robots, mTOR drugs like rapamycin, gene editing, stem cell cyro-preservation, sirtuin-activating molecules, insulin-modulating drugs like metformin and more. Some of these products are still under investigation in different clinical trials. Not only it can take many years for many of these anti-aging human trials to be completed, but thereafter, many of these anti-aging products will be too expensive for the general public and many of these products are not immune from deleterious side effects. As a consequence, risks may outweigh benefits, especially for people who are relatively healthy and are just seeking to add 30 or 40 extra years to their lifespan. Thus, waiting a few years before some of these bio-tech longevity hacks may be accessible and proven safe and effective is not cellularly or financially responsible, if only because today we have the knowledge that key holistic tools can significantly help to rejuvenate, repair and restore most metabolically impaired tissues. Holistic and Happiness medicine can also meaningfully help to offset and significantly delay Evolution’s programmed aging process.
Distinction between Accelerated and Delayed Aging
Aging is less an irreversible metabolic process of accumulated damage and systemic debilitation than a genetic and evolutionary-based “mise à mort” (death process) program that is plastic, meaning modifiable. The evidence does confirm that once we have self-replicated to both share and pass on our genes for the benefit of Community, Nature or Evolution puts in place via specific genetic expression signals a program to destroy fertility, stamina and a healthy long lifespan, especially for those who choose to live unholistically. As a result, signaling molecules that broadcast identifiable instructions inundate the bloodstream to accelerate inflammation, in particular via the Cox2 and NF-Tb pathways, the growth of debilitating senescent cells, oxidative stress and, among others, cancer. Concomitantly, youthful hormones, repair mechanisms, small RNAs, micro-proteins and the like are decelerated. (Source)
While the anti-aging industry strives to attempt to fix these problems with gene therapy and symptom-targeting drugs and supplements, we at the Optimal Longevity Institute show that both preventive care and holistic savoir-faire can promote enough homeostasis and rejuvenation for most humans to be able to reprogram and-or fine-tune the mainstream Genetic Code so that genetic expression de-activates the chronic disease genes and pathways while upregulating the healthy and longevity ones. Until proof of the contrary, all living forms eventually die, including the great tortoises and the small naked mole rats. Humans are no exception. Different from certain species of tortoises who live over 200 years, the more women age, the less fertile they become (for a species of tortoise, with age there are more & more eggs). But what most biogerontologists miss and even dismiss is happiness and holistic medicine as a meaningful vector of rejuvenation in terms of reversing the mainstream accelerated aging culture (code) to one that is characterized by a smooth healthy delayed aging process, based on holistic savoir-faire and abundance, including an abundance of simplicity, consciousness and digestive rest. Just like with conventional medicine, too many gerontologists are focused on a symptom-based approach to aging, treating one damaged organ at a time without a holistic approach. By a holistic approach, we don’t only mean a root-cause lab-test analysis of a chronic disease. Often, an oxytocin-abundant hug, an extra pay check bonus or a clear-conscious spiritual awakening will have an “anti-age” effect that is clinically superior to a sirtuin or synolitic pill. In this context, the zip code (where and with whom a person lives) can therefore “over-ride” the genetic code.
The Happiness Medicine and O.L. Institutes’ central Premise on Aging and Longevity
When young, the body is flexible, strong, fertile and repairs quickly damage. When older, the body gradually destroys itself with inflammation, eliminating nerve and muscle cells via apoptosis and more. Today, we can identify a few mechanisms of action that promote these two evolutionary states of being, one of which are circulating hormonal signals that travel in the blood’s plasma. When hormones and other blood factors emit the message “old, your self-replication time is up” we get older and vice versa. This basic premise rests on a hypothesis that has been empirically tested with success, as we will see during the development of this workshop. As a consequence, happiness and holistic medicine may be the best ever health approach to gently upregulate the youthful signals and staunchly downregulate the disease and accelerated death instructions we have allowed to be part of human Consciousness’ genetic program
The Basics of Biogerontology
“The idea is to die young as late as possible.” (Ashley Montagu)
After a brief introduction, the workshopees will be introduced to the evidence that corroborates the reality of healthy long human lifespans (in between 110 and 122 years of age). In this context, we will examine supercentenarian individuals like Jeanne Calment (who reached 122 years), the longevity valleys and blue zones as well as the scientific debates regarding maximum human lifespans. These analyses will help us to identify the key longevity factors that characterize some of these geographical areas where healthy centenarians are abundant. Thereafter, we will examine the aging and longevity biomarkers as well as the major hallmarks or biochemical pathways of aging.
Nobel Professors of Physiology whose recent findings have meaningfully enhanced the value of Rejuvenation Medicine
In this Presentation, we will review a few Nobel laureates who have greatly contributed to the understanding of the Longevity Code, from a Japanese Professor’s work on autophagy (for which he received a Nobel prize in 2016) (Source) as well as from recent discoveries regarding a Circadian clock that governs much of mammalian biology, (Source), Professor Blackburns’ discoveries on Telomerase as well as Yamanaka and John Gurdon efforts, who were awarded the Nobel Prize for Physiology in 2012 for the discovery that mature cells can be converted back in time to stem cells. (Source) Professor Horvath, who fined-tuned another biological clock called the Epigenetic clock has also helped to redirect biogerontology to one of the key hallmarks of aging, the epigenome, as well as a few other Nobel laureates.
Biomarkers (Aging and Longevity)
During the last few years, multiple efforts have been made to better quantify biological aging. One of the first institutes to work on this project are the National Aging Institute (cf. the Baltimore Longitudinal Study of Aging (BLSA)) and the N.I.H’s Nhanes survey. (Source). The European MARK-AGE brought together over 20 European countries to also contribure in this endeavor, while a group of scientists in New Zealand recently looked at 18 aging biomarkers in a cohort of young adults that were followed for 12 years. This New Zealand study, called the “Dunedin Study”, suggests that rates of aging can be measured even in relatively young adults. (Cf. Daniel W. Belsky et al., Quantification of biological aging in young adults, PNAS, Jul 2015, 112 (30) E4104-E4110). (Source)
Once we have reviewed most of the significant physical, biological and genetical (DNA) biomarkers that have been worked on, we will select the most relelvant biomarkers that appear to be the best suited to assess at any given moment a person’s biological age as well as his or her healthy lifespans predictors. These evaluations can also help to better address age-related diseases and one’s optimal longevity potential. One of the impotant challenges for future clinicians will be to integrate these aging and longevity biomarkers with the physiological and biochemical markers that are already in use in medicine.
The Epigenetic Clock
Of all of the biological clocks (telomere clock, circadian clock, hypothalamus clock etc) that can be biomarkers of aging, the Epigenetic Clock is one of the more reliable ones, recently considered by the biogerontology experts to be even more reliable than the Telomerase Shortening clock. Based on DNA methylation, histone modification and other factors, this “senescence-measuring” clock had been determined to be 98 percent accurate. (Source) Over 300 methylation sites have been correlated with biological age. Professor Steve Horvath, a biostatistician from UCLA, published a key article in which he analyzed the way gene expression changes with age. (Source) A semi-permanent factor in gene expression is methylation of the DNA, and Horvath showed that a person’s age can be determined by using a statistical template he developed to analyze which genes are methylated. UCLA professors are still working on this clock’s fine-tuning. (Source) Once this tool gets perfected and becomes better recognized, it may be a great way to monitor rejuvenation techniques, whether this supplement or that lifestyle change or drug does in fact slow or stop the biologically “programed” organismal senescence process. In this Presentation, we will show the evidence supporting this claim. To know if such and such a longevity measure is working, we would normally need many years of clinical trial experimentation to ascertain the safety and efficicacy of longevity tools. However, with dependable biomarkers, health professionals can better monitor progress at a quicker pace, a bit like with cancer biomarkers. From the holistic viewpoint, the use of guided intuition to determine the best personalized pathway to optimal longevity is still an option. But because so many people are out of synch with their intuition, tools like this epigenetic clock and other biomarkers can be useful.
Case studies of a few Humans and Animals who have significantly outlived their peers
Top: The French Mediterranean dancer, who is the Happiness Medicine Institute’s Hero, Madame Jeanne Calment, a Piscean born on February 21, 1875, is still the Optimal Longevity Champion. Having reached 122.5 years, according to her claims, she “allowed” herself to die. In other words, she could have continued to live. Her age was confirmed via birth certificate and the Guiness Record scientist-investigators confirmed this fact. In this picture, she was 120.
In this Presentation, we will study the Life and thoughts of the Mediterranean Extreme Longevity Champion Jeanne Calment whose longevity record has never been broken. (Source) We will also look at her lifestyle, her diet and her medical records that span from 111 years to 118. Thereafter, we will make an evidence-based determination as to what kept her going for over 122 years. A few other super centenarians as well as animals will be compared to this all time longevity record breaker. And yes, she drank red wine with her Med-diet meals, (with, on occasion A2 quality cheese & wild fish), had a great sense of humor and enjoyed lots of dark chocolate, up to one kilo a week (2.2. pounds). (Source) But according to Jeanne herself, French scientists and her doctor, her healthy lifespan secret was something else.
“Centenarians are the best example of extreme human longevity, and they represent a selected population in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. The study of the long-lived individual genetic profile has the purpose to possibly identify the genes and the allelic variations influencing extended life expectancy, hence considering them as biomarkers of age-related diseases onset and development. The present study shows no significant differences between allelic variations of ABO blood groups among a group of centenarians from Western Sicily”. (Source)
Are there genetic variants or determinants that account for extreme longevity in humans ?
Longevity scientists have been researching “protective longevity genes” for a long time. Some of these “life extension” genes function via cellular defense compensatory mechanisms, in particular with regard to oxidative stress, autophagy and inflammation. In this field, we will look at three of the more important families of genes that modulate age-related pathways. These are the SIRTUINS, APOEs and FOXOs (FOXO1 and FOXO3) (Cf. Willcox et al., 2006 and Soerensen et al., 2010, 2015 and Brooks‐Wilson, 2013). The variant FOXO3A for example, is found in many German centenarians as well as in a few other ethnic groups around the world, (Source). On the other hand, FOXO4 has a role in maintaining the harmful state of cellular senescence by sabotaging that specific mechanism that has been shown to selectively push senescent cells into self destruction. So not all FOXO variants have been created equal.
On the other hand, the sirtuin genes modulate noly only anti-aging pathways, but also helps with chronic diseases. (Source) And wine’s resveratrol is a sirtuin 1 activator. While APOE4 is problematic, its variant (allele) APOE2 is anti-aging. (Source)In this Presentation, we will briefly assess what is the relevance of longevity genes in relation to stochastic, environmental and epigentic factors upon which humans have control. Later on in the workshop, we will give a list of foods and supplements that can help to activate these and other longevity genes whose ribosomes produce proteins that have beneficial effects on multiple longevity pathways. (See ultra). What is important to underline at this juncture is that genes are downstream to what is quintessential: lifestyle, metabolic processes and holistic tweaking. Just like with cancer. To resolve the cancer challenge, we must focus upstream from genes. Same approach with longevity. We need to focus upstream from longevity and anti-longevity genes. Hence, the importance of rejuvenation and restorative therapies that address the root causes of aging. And by ricochet, this holistic approach helps to express (activate) the good genes and down regulate (de-activate) the harmful accelerated death genes. But before we examine these techniques, we need to better undersand the major hallmarks of biological aging.
The Biology of Aging: Understanding the Mechanisms that Spur Accelerated & Delayed Aging
“Medicine is not only a science; it is also an art. It does not consist of compounding pills and plasters; it deals with the very processes of life, which must be understood before they may be guided.” Paracelsus
To be motivated to adopt a Holistic Restorative and Rejuvenation Lifestyle, it is first necessary to understand the mechanisms that govern normal aging in relation to accelerated aging and slow holistic “delayed” aging. When we see that Lifestyle and holistic savoir-faire impact all of the major hallmarks of aging, including gene expression, it is then easier to pay attention to what is important in Life, provided one desires a healthy supercentenarian existence. But one must genuinely and vividly desire to achieve this Life potential. The supercentenarian life is not for the faint of heart. To achieve this high vibrational level of Life, resistance against toxicity and activation of holistic techniques, including in the fields of relaxation, detox, exercises, meditation, up-beat attitude, hormesis, quality nutrition, sleep and vibrant water intake, among other elements, are more important than the genetic or zip codes.
What is Biological Aging & Senescence ?
“ ..aging can be modulated by genetic pathways and biochemical processes which are evolutionarily conserved” (Lopez‐Otin et al., 2013))
Mainstream conventional non-holistic biological aging (or senescence) is characterized by a progressive loss of physiological integrity, leading to impaired function, accumulated damage, rampant frailty, complete infertility and death in an expensive hospital bed, usually after a hefty morphine drip hook-up, but a little before the morgue industry arrives. I’ve also heard some gerontolists say that aging is the declining ability to respond to stress characterized by increased homeostatic imbalances and functional degradation occurring in a stochastic (random) fashion that leads to the accumulation of cellular damage, tissue decline and death (i.e., cerebral hypoxia, i.e., lack of oxygen to the brain, is the immediate cause of all human deaths).
On the other hand, there’s the holistic way to age, where the death candidate thrives until the last weeks and thereafter, leaves his or her body in his or her sleep and-or with full consciousness on the terrain with little if any painful experience.
Because the structural bio-chemical and genetic causes of aging and chronic diseases share similar pathways and since we can control and reverse most chronic diseases with holistic and innovative medicine, it necessarily follows that aging can be less a business than a ritual celebrating the ending or crowning of a human life at it’s full potential, for now at 122 years.
Longevity scientists have been researching “protective longevity genes” for a long time. Some of these “life extension” genes function via cellular defense compensatory mechanisms, in particular with regard to oxidative stress, autophagy and inflammation. In this field, we will look at three of the more important families of genes that modulate age-related pathways. These are the SIRTUINS, APOEs and FOXOs (FOXO1 and FOXO3) (Cf. Willcox et al., 2006 and Soerensen et al., 2010, 2015 and Brooks‐Wilson, 2013). The variant FOXO3A for example, is found in many German centenarians as well as in a few other ethnic groups around the world, (Source). On the other hand, FOXO4 has a role in maintaining the harmful state of cellular senescence by sabotaging that specific mechanism that has been shown to selectively push senescent cells into self destruction. So not all FOXO variants have been created equal. On the other hand, the sirtuin genes modulate noly only anti-aging pathways, but also helps with chronic diseases. (Source) And wine’s resveratrol is a sirtuin 1 activator. While APOE4 is problematic, its variant (allele) APOE2 is anti-aging. (Source)In this Presentation, we will briefly assess what is the relevance of longevity genes in relation to stochastic, environmental and epigentic factors upon which humans have control. Later on in the workshop, we will give a list of foods and supplements that can help to activate these and other longevity genes whose ribosomes produce proteins that have beneficial effects on multiple longevity pathways. (See ultra). What is important to underline at this juncture is that genes are downstream to what is quintessential: lifestyle, metabolic processes and holistic tweaking. Just like with cancer. To resolve the cancer challenge, we must focus upstream from genes. Same approach with longevity. We need to focus upstream from longevity and anti-longevity genes. Hence, the importance of rejuvenation and restorative therapies that address the root causes of aging. And by ricochet, this holistic approach helps to express (activate) the good genes and down regulate (de-activate) the harmful accelerated death genes. But before we examine these techniques, we need to better undersand the major hallmarks of biological aging.
Senescence is not the inevitable fate of all living organisms. The discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats and the existence of species that have negligible senescence and even no biological aging have been documented for a long time.
A careful examination of the data shows that Life, of which humans are part, exudes multiple forms that experience very slow or no biological aging. Indeed, different living organisms who share the same genes as humans experience chronological decrease in mortality, for all or part of their life cycle (Cf. Ainsworth, C; Lepage, M (2007). “Evolution’s greatest mistakes”. New Scientist. 195 (2616): 36–39 Source). Species like the Hydra are quasi immortal while other species become more fertile with chronological age, like large turtles. The rock fish, like his lobster cousin can live for hundreds of years if it were not for predators and human toxic dumps. Some even exhibit negligible and even negative senescence, in which mortality falls with age, in disagreement with the Gompertz–Makeham “law” which provides that mortality rates accelerate exponentially with age.
Let us consider the Hydra. Today, the best natural scientists have not refuted that Hydra stem cells have a capacity for indefinite self-renewal. The transcription factor, “forkhead box O” (FoxO) has been identified as a critical driver of the continuous self-renewal of Hydra. (Boehm, Khalturin, Anton-Erxleben, Hemmrich, Klostermeier, Lopez-Quintero, Oberg, Puchert, Rosenstiel, Wittlieb, Bosch; Khalturin; Anton-Erxleben; Hemmrich; Klostermeier; Lopez-Quintero; Oberg; Puchert; Rosenstiel; Wittlieb; Bosch (2012). “FoxO is a critical regulator of stem cell maintenance in immortal Hydra“. Proceedings of the National Academy of Sciences. 109 (48): 19697. (Source)
Other living organisms like planarian flatworms, and certain sponges, corals, and jellyfish do not die of old age and exhibit potential immortality. (Petralia, Ronald S.; Mattson, Mark P.; Yao, Pamela J. (2014). “Aging and longevity in the simplest animals and the quest for immortality”. Ageing Res Rev. 16: 66–82. (Source).
Jellyfish are also known to defy time. The jellyfish known as Turritopsis doohmii, or more commonly, the immortal jellyfish bypasses death by actually reversing its aging process. If the jellyfish is injured or sick, it returns to its polyp stage over a three-day period, transforming its cells into a younger state that will eventually grow into adulthood all over again. (Source) Flatworms are also known for the biological “immortality”. Also called planarian worms, they are famous for their regeneration abilities. Even with a severed body, they will grow it back pronto.(Source) Then we have the Deinococcus radiodurans, a poly-extremophilic bacterium who is radiation-resistant. These immortal animals can also die and come back to life thanks to their DNA repair mechanism. According to Ira S. Pastor, “[They] can survive cold, dehydration, vacuum, and acid, and [have] been listed as the world’s toughest bacterium.”The Guinness Book of Records states that they “can resist 1.5 million rads of gamma radiation, about 3,000 times the amount that would kill a human”. As for the tardigrade, these creatures are capable of sticking around for thousands of years or even indefinitely “by entering a state of cryptobiosis, whereby their metabolism comes to a halt.” (Source).
Different Theories of Biological Aging
There are multiple theories as to why senescence occurs. Some groups of scientists posit it is programmed by gene expression changes, others that it is the cumulative damage caused by biological processes liked to mitochondrial dysfunction, ROS accumulation, cellular senescence and the P53 while still others believe that cellular senescence is the result of the body’s exhaustion of stem and repair cells in association with telomere attrition etcetera.
While there are many incertitudes in this field, what appears to be irrefutable is that the “terrain”, the “field”, the “milieu” tends to prevail over the “unit”, Life forms. For example, the same stem cells placed in three different petri dishes with a different milieu (terrain) will differentiate differently. Likewise, identical cells (like human twins) that are genetically identical, but have substantially different outside stimuli (bioterrains) will respond differently and hence have different lifespans. These facts indicate that the “terrain”, the “milieu”, the epigenetic factors play a key role in gene expression. (Ryley J; Pereira-Smith OM (2006). “Microfluidics device for single cell gene expression analysis in Saccharomyces cerevisiae”. Yeast. 23 (14–15): 1065–73. (Source)).
Cancer cells & Supercentenarians: Common threads
The current status of aging research exhibits many parallels with that of cancer research. The cancer field gained major momentum in 2000 with the publication of a landmark paper that enumerated six hallmarks of cancer (Hanahan and Weinberg, 2000), and that has been recently expanded to ten hallmarks (Hanahan and Weinberg, 2011). This categorization has helped to conceptualize the essence of cancer and its underlying mechanisms upon which good medicine can intervene.
In this perspective, the condition of cancer and aging may seem opposite processes, but in reality, they share common origins and pathways. What unites both these phenomena is the time-dependent accumulation of cellular DNA damage, which is a major hallmark of both aging and cancer. Therefore, cancer and aging can be regarded as two different manifestations of the same underlying process, namely, the accumulation of cellular damage and genomic instability. In addition, several of the pathologies associated with aging, such as atherosclerosis and inflammation, involve uncontrolled cellular overgrowth (Blagosklonny, 2008).
Furthermore, cancer and supercentenarians share a common “ally”, the telomerase enzyme. By activating its telomerase enzyme to keep telomeres long, over 90 percent of cancer cells have learnt, to become quasi-immortal. As long as they have fuel, cancer cells continuously divide thanks to the self-replicating telomerase enzyme, hence they are not subject to the Hayflick limit (50 to 70 cell divisions) or the laws of senescence death. (Source). As a result, they don’t age. Similarly, those supercentenarians who reach long lifespans also have more active telomerase and longer telomeres, while children who age very quickly (like this proragia girl in the picture below) have very short telomeres.
Top: A young infant girl who suffers from Proregia syndrome. She is only around 2 years old, but appears much more. Also known as Hutchinson-Gilford syndrome, this disease is genetic. It is characterized by accelerated aging that is accompanied with the age-related diseases. The mean age at death of these patients is 12.5 years. These children die “old” before 15 or 20, at which point they look like 80 years old.
Case study A: Ultra rapid metabolic accelerating-aging
To better understand a few of the mechanisms behind normal and delayed aging, it’s useful to study cases where aging proceeds very fast and very slow. In humans, there’s a genetic disease called Proregia syndrome, also known as Cockayne syndrome (CS), Hutchinson-Gilford syndrome , Werner’s syndrome (WS), Bloom’s syndrome and trichothiodystrophy. All of these diseases are autosomal recessive disorders with progeroid symptoms. These disorders are rare genetic diseases characterized with extreme premature aging and a shortened life expectancy. All of the hallmarks of aging are manifested, including cessation of growth, liver, kidney and bone abnormalities, retinopathy, hearing loss, sarcopenia, neurodegeneration, sensitivity to UV light, and a premature aged appearance due to kyphosis, baldness, loss of subcutaneous fat, and, inter alia, dry wrinkled skin. (Source)
Children with progeria have a mutation on the gene that encodes for lamin A, a protein that holds the nucleus of the cell together. This protein is also known as progerin. The defective protein makes the nucleus unstable and short-lived. (Source) The mean age at death of these patients is 12.5 years. (ibid) There is currently no treatment for these syndromes and the clinical management of patients is essentially palliative. Although some differences exist in the pathology of these conditions, the central causal factor of all these syndromes lies in impaired genome maintenance due to DNA repair deficiencies and genome instability. (Source). Two other hallmarks of aging, the depletion of stem cells as well as telomeres attrition, have also been identified to correlate with this disease.
Top: A 16 years old little girl who stopped growing at 11 months.
Case Study B: Ultra-slow Growth: Children who do not Age, genetically “frozen” in Time
In contradistinction to children who senesce fast, there are other children who don’t senesce at all or extremely slowly. They also eventually die young, from complications. The understanding of this medical phenomenon is recent, it started only in 2009 with the report about 16-year-old girl who seemed to be “frozen in time.” She was the size of an infant, with the mental capacity of a toddler rather than a teenager. (Source) See also Brown, Bob (23 June 2006). “Doctors Baffled, Intrigued by Girl Who Doesn’t Age”. Health. ABC News.
This genetic disease used to be called Syndrome X, but now it is labeled as “neotenic complex syndrome” (NCS). After having sequenced the genome of a few of these diseased children, the researchers found key de novo mutations (DNMs) in two development genes ((DDX3X and HDAC8), located on the X chromosome and affecting transcription regulation and chromatin modification, inter alia. (Source). See also Walker, R.; Pakula, L.; Sutcliffe, M.; Kruk, P.; Graakjaer, J.; Shay, J. (2009). “A case study of “disorganized development” and its possible relevance to genetic determinants of aging”. Mechanisms of ageing and development. 130 (5): 350–356. (Source))
Roundworms Experimentations confirm: aging and lifespan is regulated in part through the insulin/IGF-1 and mTOR pathways.
Top: the transparent nematodeC. elegans.This roundworm is one of the most studied for neurodegeneration and longevity. Scientists have been able to significantly extend its lifespans by tweaking its genes.
In order to study key age-related genes, gerontology specialists examine many different types of genes that come from different animals. According to the GenAge database of aging-related genes, there are over 1800 genes altering lifespan in model organisms: 838 in the soil roundworm (Caenorhabditis elegans), 883 in the bakers’ yeast (Saccharomyces cerevisiae), 170 in the fruit fly (Drosophila melanogaster) and 126 in the mouse (Mus musculus). (Source).
The first mutation found to increase longevity in an animal was the age-1 gene in Caenorhabditis elegans. (Top Picture) Michael Klass discovered that lifespan of C. elegans could be altered by genetic tweaking (mutations), but Klass believed that the effect was due above all to the reduced food consumption (calorie restriction) regime the Elegans worm was put under. He published his results in 1983. (Source). Thomas Johnson later showed that life extension of up to 65% was due to the mutation in gene age-1 itself rather than due to calorie restriction. The age-1 gene encodes the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K). (Source)
A decade after Johnson’s discovery, one of the two genes that are essential for dauer larva formation, the “daf-2”, once mutated, was shown by Cynthia Kenyon to double C. elegans lifespan. Nature. 366 (6454): 461–464 (Cf, Dorman, Jennie B.; Albinder, Bella; Shroyer, Terry; Kenyon, Cynthia (1995). See also “The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans”. Genetics. 141 (4): 1399–1406). See (Source).
The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. (Source). DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. (Source). Subsequent genetic modification (PI3K-null mutation) to C. elegans was shown to extend maximum life span tenfold. (Source) See also Shmookler Reis RJ, Bharill P, Tazearslan C, Ayyadevara S (2009). “Extreme-longevity mutations orchestrate silencing of multiple signaling pathways”. Biochimica et Biophysica Acta. 1790 (10): 1075–1083. (Source)
The IGF-1 & mTOR pathways
Research into the interaction between diet and the insulin/IGF-1 pathway has shown sugar intake to be negatively correlated with DAF-16 activity and longevity. In this perspective, Wild type C. elegans was fed a diet that included 2% glucose. It was subsequently shown that Daf-16 activity was reduced and lifespan was shortened by 20% compared to worms fed on glucose-free media. These findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms. (Lee, S. J.; Murphy, C. T.; Keyon, C. (2009). “Glucose shortens the life span of c. elegans by downregulating daf-16/foxo activity and aquaporin gene expression”. Cell Metabolism. 10 (5): 379–391. (Source)).
Many studies in yeast, and in a wide range of multicellular lower and higher organisms, have shown that caloric restriction (CR) simultaneously increases lifespan while improving mitochondrial activity while the inhibition of nutrient sensing (NS) signaling pathways, such as the Insulin/IGF-1 (Source) and mechanistic target of rapamycin (mTOR) (Source) pathways, led to similar results.
Several metabolic pathways and molecules regulate lifespan in response to nutrient availability and balance energy expenditure with mitochondrial function. The insulin and IGF1 pathway was the first evolutionarily conserved pathway shown to regulate lifespan. Mammalian target of rapamycin (mTOR) signalling has also been implicated (Source A, Source B). There is increasing recognition that these metabolic pathways are intimately interconnected. For instance, AMP-activated protein kinase (AMPK), which is a central sensor of energy homeostasis that modulates mTOR signalling, activates forkhead box O (FOXO) transcription factors, which are targets of insulin and IGF1 signalling. This increases the expression of genes that are involved in stress resistance and energy balance (Source). Decreased activity of the insulin and IGF1 pathway is associated with improved mitochondrial function, as demonstrated in long-lived Ames mice (which have very low levels of IGF1) and in mice with decreased levels of insulin receptor substrate 2 (IRS2) (Source) Reduced insulin and IGF1 signalling results in the activation of FOXO transcription factors, which induce the expression of antioxidants, such as manganese superoxide dismutase (MnSOD) and catalase; accordingly, FOXO-deficient mice display increased levels of ROS and stem cell depletion (Source A,Source B). The 20 percent shortening of the C Elegans’ lifespan with 2 percent glucose in the diet observation only suggests that sugar may be a problem with regard to longevity optimization. The worm was not fed human complex carbs, let alone organic fresh complex carbs, furthermore, healthy carbs for humans may fuel longevity pathways instead of a shortening lifespan because sugar is different from healthy carbs and mammals like humans are different from worms, even if we share common genes, biochemical pathways and wiggly manners. At this juncture, what the facts appear to be suggesting is that in higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 and mTOR pathways.