Tag: Aging

The diminishing returns of reactive medicine

In an article for Slate, Jay Olshansky argues in favor of a position that one would expect to be common sense at this point:

While we can extend life in aging bodies through behavioral improvements and medical treatments, the time has arrived to acknowledge that our current model of reactive medicine, of trying to treat each separate disease of old age as it occurs, is reaching a point of diminishing returns.

So what is the reason why vast amounts of money are spent on research to treat age-associated diseases but so little on eliminating or mitigating aging as such? Why is this “one-disease-at-a-time model” so dominant? One reason might be that most people believe that overcoming one specific manifestation of aging is easier to do than overcoming aging itself. Not surprisingly, most academic and commercial research is shaped by short term ambitions or short-term financial interests.

Many people who deal with serious age-associated diseases hope that a cure can be found within their lifetime.  This is not so strange if you consider that many people who do advocate meaningful rejuvenation research are technological optimists who think the same thing about overcoming aging. In that sense, people show little interest in supporting research that has little personal benefit to them or close relatives. This is further evidenced by the fact that people are more inclined to contribute to anti-aging efforts that promise benefits in their lifetime. This in turn provokes criticism from mainstream scientists of not being realistic, which further discredits the field.

But as Olshansky indicates, the diminishing returns of the approach to just fight the symptoms of aging should force people to change perspective. Olshansky also observes  that “manufacturing survival time in the absence of decelerated aging” can produce a lot of hardship and suffering in old age:

It’s important to acknowledge the fundamental differences between disease and aging. Although age-associated changes in the body produce an increased risk of disease, the reverse is not true. That is, reducing the risk of disease has no influence on biological aging. Thus, if a population is preserved with increasing efficiency by advances in technology that reduce the risk of disease, those saved will live into increasingly later sections of the lifespan where aging takes a greater toll on body and mind. Life extension achieved in this way could extend old age by exposing survivors to the high-risk conditions of frailty that are common, and largely immutable, near the end of life—the very outcome that medicine and public health practitioners are trying to avoid.

For people who have made cryonics arrangements, there is another danger; the possibility of life extension at the price of increased vulnerability to identity-destroying diseases.  There is no shortage of cryonics patients with Alzheimer’s or impaired brain function. As much as we would like to deny it, there could be a disturbing trade-off between life extension and true personal survival as long as treatments for neurodegenerative diseases are not available.

Cryonics Oregon June Meeting with Aubrey de Grey and Ben Best

On June 6th the next Cryonics Oregon meeting will coincide with a downtown Portland aging conference. As a result we have been successful in persuading Cryonics Institute President Ben Best and Alcor member and biogerontologist Aubrey de Grey to attend our meeting. The theme of the evening will be “Strategies for Life extension and Rejuvenation: A Discussion with Aubrey de Grey and Ben Best.”

Dr. Aubrey de Grey will present a brief synopsis of his Strategies for Engineered Negligible Senescence (SENS) for regeneration and rejuvenation. Ben Best will reply with his view of shortcomings of the SENS approach, and how these shortcomings can be addressed. Discussion will include such matters as biomarkers of aging, mechanisms of aging, use of dietary supplements and the relevance of cryonics.

Date:  Sunday, June 6, 2010
Time: 7:30pm – 10:00pm
Location: Roots Organic Brewing
Address: 1520 SE 7TH, Portland, OR

This will be no ordinary Cryonics Oregon meeting! Promotional materials from Alcor, CI, and SENS will be there as well.

To cover the rent of the space a minimum donation of $5.00 per person will be collected.

Attendees under 21 are allowed until 10:00 pm.

It is very important for everyone to RSVP as soon as you know if you can make it or not so we can get a good idea of attendance.

The case for cryonics

The biology-of-aging blog Ouroboros has posted a skeptical post about cryonics that is highly representative of how most biological scientists respond to questions about cryonics. The discussion of cryonics is largely reduced to a discussion of the technical feasibility of suspended animation and resuscitation requirements. But suspended animation is not cryonics. Cryonics should be discussed in the broader context of decision making under uncertainty. People who have made cryonics arrangements are more than aware that contemporary science is not able to vitrify and resuscitate a complex organism. To them the central question is whether we can reasonably expect that future technologies will be able to repair the injury that is produced by contemporary cryopreservation technologies and rejuvenate the patient. That is the “probabilistic” side of the issue. On the utility side of the equation is nothing less than personal survival.

This does not mean that cryonics should be approached as a form of Pascal’s Wager in a vacuum. Experimental evidence from fields such as cryobiology, biogerontology and nanotechnology plays an important role in shaping our expectations about the technical feasibility of the resuscitation of cryonics patients. Many biologists, however, feel confident that they can make a case against cryonics without even bothering to examine the current state of the field. For example, how many biologists know that the latest generation of vitrification agents have low enough toxicity to permit vitrification of animal brain slices with retention of electrical activity?

The author writes:

The field could take a lesson from the dawn of modern biogerontology back in the early 1990s: Acknowledge the mind-bending complexity of the challenge. Create model systems for cryonics, using the best tools from the vast edifice of modern biological knowledge.

But that is exactly what the cryonics field has done. Millions of dollars have been devoted to identify low-toxicity vitrification agents and protocols to preserve viability after pronouncement of legal death.  Progress in the cryopreservation of complex organs (including the brain) has been so successful that the vitrification agent that is currently used by the Alcor Life Extension Foundation, 21st Century Medicine’s M22, is the least toxic vitrification agent in the peer reviewed cryobiology literature to date.

The author is correct that the project of cryonics is of “mind-bending complexity.” One major reason for this is that the resuscitation of most cryonics patients will require successful rejuvenation. As a result, cryonics advocates are quite interested in anti-aging research. But whereas modern biogerontology, not unlike macroeconomics, is still plagued by ongoing (technical) debates about even the most basic definitions employed in the field, or engaged in discussions about what constitutes the most effective approach to pursue rejuvenation, the cryonics field has moved from the practice of the crude freezing of patients to the pursuit of long term care at cryogenic temperatures without ice formation and minimal ischemic injury.

Perhaps there is good reason for this difference in success rate. As mathematician and cryonics advocate Thomas Donaldson pointed out, anti-aging research faces conceptual and methodological challenges that cryobiology research does not. Perhaps the time scale to develop and validate effective anti-aging strategies is similar to that of developing a mature technology that can manipulate matter at the molecular level. If this is the case, rejuvenation research could benefit from being pursued as a broader evolutionary bio-nanotechnology research program.

The discussion of cryonics is most fruitful where logic and empirical science meet.  We need to employ the tools of logic to guide coherent decision making and we need the results of experimental science to provide empirical weight to guide those decisions. In a world where knowledge is recognized as probabilistic, and where death is recognized as a biological process that can be halted through the use of low temperatures, the decision to make cryonics arrangements can be rational and life-affirming.

Ben Best on nuclear DNA damage and aging

The June 2009 issue of Rejuvenation Research features an article by Cryonics Insitute President Ben Best about the involvement of nuclear DNA damage in the aging process:

Abstract

This paper presents evidence that damage to nuclear DNA (nDNA) is a direct cause of aging in addition to the effects of nDNA damage on cancer, apoptosis, and cellular senescence. Many studies show significant nDNA damage with age, associated with declining nDNA repair, and this evidence for the decline of nDNA repair with age is also reviewed. Mammalian lifespans correlate with the effectiveness of nDNA repair. The most severe forms of accelerated aging disease in humans are due to nDNA repair defects, and many of these diseases do not exhibit increased cancer incidence. High rates of cellular senescence and apoptosis due to high rates of nDNA damage are apparently the main cause of the elderly phenotype in these diseases. Transgenic mice with high rates of cellular senescence and apoptosis exhibit an elderly phenotype, whereas some strains with low rates of cellular senescence and apoptosis show extended lifespan. Age-associated increases of nDNA damage in the brain may be problematic for rejuvenation because neurons may be difficult to replace and artificial nDNA repair could be difficult.

HT Longevity Meme

BioTime's quest to defeat aging

Unless you are a long-time cryonicist or a surgeon, you may not have heard of BioTime before. This company, recently profiled for its innovative stem cell research in Life Extension Magazine, is best known for producing the blood-volume expander Hextend, which was initially developed by Trans Time, an early cryonics company performing ultra-profound hypothermia research. Realizing the potential for Hextend’s conventional medical applications, BioTime was formed and, as they say, the rest is history.

These days, BioTime does its best to distance itself from its early history. As documented in this 2004 WIRED magazine article, BioTime prefers to downplay its (prior) relationship with Trans Time even though the association is well documented. Furthermore, their development of products like Hextend and its modification HetaCool, which can be used as a blood substitute to allow cooling to ultra-profound hypothermic temperatures for heart and brain surgery, as well as newly-developed HetaFreeze, a cryoprotectant solution used for long-term tissue and organ preservation at sub-zero temperatures, point to their cryonics past.

But things are changing at BioTime. Under the direction of CEO Dr. Michael West, and capitalizing on the highly successful sales of Hextend and related products, the company is now heading in a new direction: regenerative medicine. Dr. West, who received his Ph.D. from Baylor College of Medicine in 1989 concentrating on the biology of cellular aging, is pushing the envelope of aging research by developing new forms of stem cells that can be used to reverse cellular aging, perhaps eventually leading to the ability to reverse aging of the entire human body.

In “Regenerative Medicine Breakthroughs: Will BioTime Reset the Clock of Aging?” (November 2008), Life Extension Magazine documents Dr. West’s mission — to understand how to make somatic (i.e., body) cells immortal and then apply this technology to the treatment of aging and aging-related diseases. BioTime is now driven by the potential for stem cell therapy to repair and regenerate organs and tissues and, if possible, to radically extend human lives.

To understand the problem of cellular aging, we must first know what happens to cells as they age. One of the most important contributions in this field was first made by Alexy Olovnikov in the early 1970s, who proposed that the DNA sequence at the ends of each chromosome (called a telomere) shortened each time a cell replicated. Once the telomeres “ran out,” the cell stopped dividing. Olovnikov also theorized that germ (i.e., reproductive) cells, whose telomeres never shorten, do not age due to the production of an “immortalizing enyzme.”  Dr. West became so convinced of Olovnikov’s theory that he formed a company called Geron to investigate it further. As reported by Life Extension Magazine:

“Forty million dollars later,” West recalls, “the gamble paid off.” West’s group had in fact produced Olovnikov’s mysterious enzyme, now known as telemorase, because of its ability to continuously spin out the vital strands of telomere DNA that keep germ cells immortal.

However, getting telemorase into aging cells is easier said than done. Instead of attempting what basically amounted to gene therapy, Dr. West decided to take another route to cell immortalization: stem cell therapy. Because embryonic stem cell research has been so controversial, Dr. West and his team at BioTime are using a technique developed by researchers at Kyoto University to create stem cells from aged somatic cells. In this procedure, transcription factors are removed from egg cells and placed in somatic cells, which transform back into colonies of stem cells over a few weeks’ time, effectively reversing the aging clock in those cells. These cells are then called induced pluripotent stem cells (iPS). They function exactly like embryonic stem cells, but do not come from an embryo.

“And since numerous papers on iPS have now shown switching on the telemorase gene in these cells,” continues Dr. West, “I believe that within the next 12 months, the scientific community will have documented, for the first time ever, the reversal of aging of a human cell.”

Dr. West’s team at BioTime still has a long way to go, however. For starters, they are trying to figure out how those stem cells “decide”  what type of cell to become. With this information, the researchers can better direct stem cells in regenerative therapies to the correct tissue or organ needing repair. Reversal of aging of distinct cell populations could lead to reversal of aging of the entire human body.

Of course it should be noted that one of the many scientific feats cryonics depends upon to succeed is regenerative medicine: it would not be ethical or practical to revive an aged cryonics patient to live in a frail and diminished state. So it seems that BioTime may eventaully be reunited with its roots….

Antioxidant skepticism

At the blog Fight Aging!, Reason draws attention to the possibility that taking large amounts of antioxidant supplements may not necessarily be an improvement:

Our biology is complex – why would we expect that successfully modifying it with chemicals would be as simple as eating those chemicals? Ingesting antioxidants in the hope of benefit because they happen to do certain things in certain portions of your biochemistry is magical thinking given the evidence on the table to date.

And as the author points out, and contrary to popular perception, free radicals play positive roles in the human body as well. A similar point was made by critical care researcher and cryonics activist, Dr. Steve Harris on usenet in 2002:

Free radicals are the signals used by the body’s inflammatory system, which is necessary for infection-fighting, normal healing, and for fighting some (not all) kinds of cancer.  Free radicals (including deliberately produced ones like NO) aren’t just garbage to be expunged in every possible way you can think of, but rather instead are often important signals, not to be ignored. You can’t just willy-nilly shotgun them, and the system which uses them, out of existence for long, without expecting to pay a price. Nature didn’t give it all of that complicated radical-producing and radical-sensing machinery to you, for nothing.

Dr. Harris himself observed the price that may be paid when he participated in the Critical Care Research canine cerebral resuscitation experiments:

I’ve given large doses of vitamin E, melatonin, PBN, NOS inhibitors, COX inhibitors, basically the anti-radical anti-inflammation works, to dogs in resuscitation trials. This works great on the brain but occasionally I see a dog get pneumonia, and some of them die from it, with complete lung consolidation, in as little as 12-24 hours, despite heavy IV antibiotics. And in a very odd way: no fever, no left-shifted neutrophils, no increased heart rate, no shock (except at the hypoxic end). The last time I saw anything like that as a physician was treating leukemic patients with no neutrophils. These dogs have neutrophils, but they’re just not working.

Aggressive antioxidant treatment has a place in the treatment of stroke and cardiac arrest but to implement such an aggressive regime in the hope of fighting aging may be wishful thinking at best, and dangerous at worst. In general, many claims about the beneficial effects of dietary supplements should be approached with skepticism.

Any credible future treatment to slow or reverse aging will require interventions that specifically target the mechanisms of aging and/or remove their damaging effects without disturbing the general biochemistry of the human body. Whether such interventions will be possible without advanced nanomedical modification of human biology remains to be seen.

No disease in the brain of a 115-year old woman

In August 2008, Neurobiology of Aging published the interesting observations of den Dunnen, et al. of the post-mortem body of a 115 year old woman, which showed no evidence of atherosclerosis. Her brain was devoid of the amyloid plaques characteristic of Alzheimer’s disease and neural density was on par with healthy persons 60-80 year of age. Pre-mortem psychological testing of the woman at ages 112 and 115 found her cognitive abilities to be well above average, scoring better than the average healthy 60-75 year old. Indeed, the authors describe her repeatedly as “alert and attentive” and interpret their findings as follows:

“Our observations indicate that the limits of human cognitive function extend far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentenarians, is not inevitable.”

This lack of pathophysiology and retention of mental abilities in old age is encouraging and should motivate us to take the best care of our bodies as possible, so that our latest years remain some of our best ones. However, it should be noted that while the woman’s Mini Mental State Examination (MMSE) score only dropped one point (from 27 to 26) from age 112 to 115, and her immediate recall ability and orientation did not deteriorate, she performed worse at age 115 at more complex tasks such as those testing working memory and mathematical calculation skills. In addition, though no amyloid deposits were found in her brain, the other hallmark of AD, neurofibrillary tangles, were observed in the medial temporal lobe, possibly indicating the very earliest stages of AD.

While brain disease at 100 may not be inevitable, and we will certainly enjoy our healthy lives as long as we have them, ultimately even the healthiest supercentenarians succumb to the progression of aging and its entourage of aging-related diseases. Cracking the mystery of aging will require multiple approaches, and studies of the oldest-lived among us provide clues as to which lines of inquiry are the best leads to follow.

Recent developments in the treatment of Alzheimer's

The full text of the Life Extension Foundation magazine article (August 2008) describing the use of Enbrel for the treatment of Alzheimer’s disease and announcing LEF’s new Enbrel trial, is now available. As previously discussed, Enbrel (entanercept) has been shown to provide immediate benefits in Alzheimer’s patients, improving memory performance and less frustration and agitation within minutes of treatment.

The more recent publication (pdf document) of additional data from the same patients in the previously reported six month Phase II trial adds further evidence to these results, specifically noting a rapid improvement in the verbal fluency of patients undergoing weekly perispinal Enbrel injections. Additionally, case studies of two more patients are given in the text of the report, and a stronger case for carrying out larger scale studies (including Phase III clinical trials) is made.

A blog post at Al Fin reports on other promising Alzheimer’s treatments such as the drug Rember, which “appears to target ‘Tau tangles’ in the portion of the brain most active in memory formation.”

TNF-alpha modulation in Alzheimer's patients

More than a decade of basic research and clinical evidence now implicates inflammatory processes in the pathogenesis of Alzheimer’s disease (AD). TNF-alpha is a pro-inflammatory cytokine, also known as the “master regulator” of the immune response, and is the key initiator of immune-related inflammation in the brain. Much evidence has linked excess TNF-alpha to the development of AD, including the demonstration of 25-fold elevated levels of TNF-alpha in the cerebrospinal fluid of AD patients and the finding that beta-amyloid (the main constituent of the amyloid plaques found in the brains of AD patients) stimulates the secretion of TNF-alpha, which in turn induces beta-amyloid production in a vicious positive-feedback loop. This beta-amyloid-induced neuroimflammation has been shown to result in neurotoxicity and to upregulate other inflammatory mediators in the brain, including interleukin (IL)-1 beta, IL-6, and nitric oxide.

To examine the effect of downregulating this inflammatory process, a group of researchers performed a 6 month pilot study in 2006 to determine the effect of modulating TNF-alpha in AD patients using the specific anti-inflammatory agent entanercept (Enbrel). Enbrel selectively inhibits the biologic activity of TNF-alpha by binding to TNF-alpha and preventing its interaction with cell-surface TNF receptors.  Entanercept is already FDA approved for the treatment of such diseases as rheumatoid arthritis, psoriasis, and psoriatic arthritis.

Fifteen patients with mild to severe AD were evaluated before treatment began and once a month thereafter for six months using three standard measures of cognition: the AD Assessment Scale-Cognitive subscale (ADAS-Cog), the Severe Impairment Battery (SIB), and the Mini-Mental State Examination (MMSE). Treatment consisted of a total dose of 25 to 50 mg of Enbrel in sterile water per week via interspinous injection. This injection between two cervical vertebrae is hypothesized to improve flow of the drug to the central nervous system (CNS). All patients in this pilot study improved significantly on all assessments of cognitive ability, which is particularly amazing given the cognitive decline that would normally be expected of an AD patient over the course of six months.

As mentioned, this pilot study was approved to evaluate patients only at monthly intervals. However, during this six-month study and over the course of their clinical experience since the pilot study, the researchers noted “an unexpected and largely unprecedented clinical phenomenon… a noticeable clinical improvement within minutes of perispinal entanercept administration.” To validate these observations, the researchers performed a case study in 2008 in which a patient with severe AD was evaluated prior to, ten minutes after, two hours after, and one week after Enbrel administration.

Prior to treatment the patient had been unable to recall his birthday, his father’s occupation, or the names of any of the physicians treating him. He was not oriented to the calendar date, day of the week, year, place, city, or state. Ten minutes after receiving an injection of Enbrel, the patient correctly identified the state as California and his demeanor was observed to be calmer and more attentive. His responses to questions were less effortful, as well.

At the 2-hour post-evaluation, the patient was able to recall the name of his evaluator and was able to identify the month, day of the week, place, and name the state of California. He was slightly off on the calendar date and year, but “appeared more aware of his deficient performance.” The patient’s scores on all mental tests also improved dramatically. These improvements were maintained over the course of a week, whereupon he was evaluated again before receiving his next Enbrel dose. The patient continued to receive a weekly dose of Enbrel for a total of 5 weeks and was re-evaluated at 7 weeks (fourteen days after his last dose). His improvement in all areas of cognitive performance was marked and significant.

An important consideration when treating a patient with Enbrel, however, is that it is immunosupressive and as such leaves the patient at high risk of morbidity if they acquire an infection. This is especially important in late-stage Alzheimer’s patients, who are generally elderly, frequently visit hospitals/treatment centers, and live in community environments, making them particularly susceptible to community-acquired infection.

Following up on the publication of these unprecedented findings, the Life Extension Foundation recently published a review of both Enbrel pilot studies and the initial results of their own pilot study involving a 91-year-old female AD patient with severe cognitive deficits, who has also shown marked improvement in cognitive ability. The Life Extension Foundation is now eager to “launch an expanded study with the objective of measuring the long-term effects of weekly Enbrel injections plus nutrients that help suppress the production of excess TNF-alpha.” These trials are aimed at treating early-stage AD patients, and weekly Enbrel injections will be given in the Fort Lauderdale area.

To inquire about enrolling in this new study, contact the Life Extension Foundation.

Insurance against death through cryonics

Let’s face it: we’re all (still) getting older, and aging leads to death. This is a major reason for cryonics’ existence — to preserve ourselves, usually in an aged, diseased, and/or deteriorated state, until medical science is capable of curing our ailments and prolonging our lives. Because many people (especially young cryonics supporters) tend to think that they will benefit from radical life extension therapies in their own lifetime, some choose to forgo making early cryonics arrangements. As discussed in a recent post, even if aging is ended or reversed there will remain a non-trivial risk of death by accident or other fatal incidents. Others who support cryonics but endlessly put off making their own arrangements also take an enormous risk in securing their own cryopreservations. It is important to be an activist for your own cause, too, after all.

That most people do acquire the financial means and/or appropriate insurance coverage to make arrangements as soon as they determine that they want to be cryopreserved is a cornerstone upon which cryonics providers rely to operate as efficiently as possible. The fact is that life insurance is easiest and cheapest to obtain when you are young and healthy. In an age where people nonchalantly dole out hundreds of dollars a month for their cell phone usage, life insurance coverage that will pay out the required amounts for your cryopreservation upon legal death is a trivial payment (on the order of $20-80/mo for a healthy young adult). Even if you are not totally sure yet whether you want to be cryopreserved, obtaining insurance at a young age that can provide for your cryopreservation is a wise move. Arriving on the doorstep of a cryonics provider as a “last minute case” is not advisable, since these are often the most demanding and controversial cases, and are also frequently subject to family interference.

Unfortunately, there are situations in which persons who have been dedicated to cryonics for many years fall upon hard times or are otherwise disposed of the ability to maintain their cryonics arrangements. For these legitimate cases, a plea for help can be raised when presented with adequate information concerning the person, their involvement in cryonics, and the nature of the circumstances leading to their disability to provide funding for cryopreservation. Of course, those who are already disabled or terminally ill before hearing about cryonics make up a good proportion of these legitimate claims, as well.

However, some of these “pleas for help” are not infrequently issued to the general cryonics populace at large via cryonics-specific Internet message forums, with little to no circumstantial information provided to assess the validity of the request. Such requests leave a lot to be desired in terms of properly addressing the need of the person desiring assistance, and devalue the importance of acquiring and maintaining cryonics arrangements throughout life, so they are not dependent upon others when bad times finally do befall them.

Looking forward, the last thing cryonics providers need are multiple series of last-minute cases and daily fundraising appeals when the “Singularity” turned out not to be as near as some people might have thought….