Category Archives: Longevity Medicine

Time here looks at Ray Kurzweil's timeline for the development of biotechnologies that can defeat aging: repair the old, remove biological damage, and eliminate frailty and age-related death. "The Singularity isn't just an idea. it attracts people, and those people feel a bond with one another. Together they form a movement, a subculture; Kurzweil calls it a community. Once you decide to take the Singularity seriously, you will find that you have become part of a small but intense and globally distributed hive of like-minded thinkers known as Singularitarians. ... At the 2010 summit, which took place in August in San Francisco, there were not just computer scientists but also psychologists, neuroscientists, nanotechnologists, molecular biologists, a specialist in wearable computers, a professor of emergency medicine, an expert on cognition in gray parrots and the professional magician and debunker James 'the Amazing' Randi. ... After artificial intelligence, the most talked-about topic at the 2010 summit was life extension. Biological boundaries that most people think of as permanent and inevitable Singularitarians see as merely intractable but solvable problems. Death is one of them. Old age is an illness like any other, and what do you do with illnesses? You cure them. Like a lot of Singularitarian ideas, it sounds funny at first, but the closer you get to it, the less funny it seems. It's not just wishful thinking; there's actual science going on here. ... People have begun to realize that the view of aging being something immutable - rather like the heat death of the universe - is simply ridiculous. It's just childish. The human body is a machine that has a bunch of functions, and it accumulates various types of damage as a side effect of the normal function of the machine. Therefore in principal that damage can be repaired periodically. This is why we have vintage cars. It's really just a matter of paying attention. The whole of medicine consists of messing about with what looks pretty inevitable until you figure out how to make it not inevitable." I don't see it as plausible that we'll have everything in hand by 2045, but if we make a good start now, then we could have enough to put us into actuarial escape velocity - gaining life expectancy faster than we age, and thus able to wait for far better technologies that arrive later.

Link: http://www.time.com/time/printout/0,8816,2048138,00.html

The early posts at Chronosphere are well done and worth reading. The theme is a detailed and picture-strewn look at the history of cryonics, mixed in with considerations of our presently imperfect society and where it might be going next: "Chronosphere is your gateway to a fundamentally new way of living - in pursuit of physical immortality in a world of our own making - free from the tyranny of time, and the burden of injustice. Chronosphere will explore and create interfaces with the scientific, technological, social and moral resources needed to achieve these ends. Because we are all at risk of dying, cryonics will be a central focus of Chronosphere for the foreseeable future, but will be by no means be the only technology explored here. Interventive gerontology, with a strong emphasis on immediate, or very near term interventions to slow cognitive aging, will also be explored in detail. Join us on our quest to transcend the limits of time!"

Link: http://chronopause.com/

By virtue of the fact that very large sums of venture capital, big pharma investment, and public funding have been sunk into the examination of sirtuins in connection with longevity in mammals, I think we'll see a strong sirtuin research contingent in the scientific community for some years to come - and this regardless of the ultimate merits of this work. While there are promising signs that sirtuins may do something useful in terms of enhancing cellular housekeeping, after some years of research we have yet to see any of the promise of slowed aging that looked possible at the outset. See, for example:

• A Possible Reason For Sirtuin Uncertainty
• Critiquing the Sirtuin Model of Calorie Restriction

Research and development always takes longer than expected, but at this point I look at research into sirtuins as an early step forward on a much longer road - a part of the foundations of some later work, and producing little of direct use in and of itself. The newer technologies and newer companies who work on the same strategy of slowing aging via identification of ways to manipulate metabolism will leap over the work of the last five years, producing a hundred-fold more genetic and biochemical data in the process. Biotechnology is advancing so rapidly that each generation of development is made obsolete before it even hits its stride. It will be interesting indeed to see what comes after the present generation of biotech startups like Genescient and Halcyon Molecular.

But back to sirtuins: here is an optimistic open access paper from researchers who do see a bright future for the development of sirtuin-based therapies.

How does aging occur? Can we delay the aging process? These are questions that have been asked for hundreds if not thousands of years.

...

Aging is one of the most fundamental biological processes. It results in a decline in physiological function and an increased risk for pernicious diseases such as cancer. Oxidative stress has been proposed as a major cause of aging, but experimental tests of this hypothesis have been discouraging. Calorie restriction (CR) prevents age-related decline, but there are still gaps in our knowledge of the exact mechanisms underlying this feat. Finally, a tenuous balance exists between aging and cancer, calling for a search for interventions that prevent both aging and cancer. Recent work on the mammalian sirtuin SIRT3 has shed light on these long-standing issues and suggested new approaches to ameliorate the ravages of aging.

You might look back into the Fight Aging! archives for a quick overview of the relevance of SIRT3 to oxidative stress and longevity:

This research group proposes that Sirt3 acts on longevity through increasing antioxidants - we should all be appropriately skeptical, given the very mixed evidence for links between cellular antioxidants and longevity. That said, Sirt3 is located in the mitochondria, and the demonstrations of extended life spans through increased antioxidants have involved targeting those antioxidants to the mitochondria.

When considered in the broader context, a great many lines of research turn to point towards our mitochondria and the damage they suffer over time. All the more reason to direct greater efforts towards nascent mitochondrial repair technologies rather than yet more metabolic tinkering.

You might recall that the olm (Proteus anguinus) is a type of small salamander that lives as long as we do. Here researchers point out that olm life span is inconvenient for some theories of aging: "Recent work on a small European cave salamander (Proteus anguinus) has revealed that it has exceptional longevity, yet it appears to have unexceptional defences against oxidative damage. This paper comes at the end of a string of other studies that are calling into question the free-radical damage theory of ageing. This theory rose to prominence in the 1990s as the dominant theory for why we age and die. Despite substantial correlative evidence to support it, studies in the last five years have raised doubts over its importance. In particular, these include studies of mice with the major antioxidant genes knocked out (both singly and in combination), which show the expected elevation in oxidative damage but no impact on lifespan. Combined, these findings raise fundamental questions over whether the free-radical damage theory remains useful for understanding the ageing process, and variation in lifespan and life histories." Yet there are still the studies demonstrating extended life span through targeting antioxidants to mitochondria, which imply that at least so far as those cellular structures are concerned, oxidative damage is very important. It may be that the olm, like naked mole rats, has mitochondria that are highly resistant to damage in comparison to other species.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21290398

A fair chunk of degenerative aging is caused by the accumulation of various kinds of damaging biochemicals, and here dry macular degeneration is added to that list: "A team of researchers, led by University of Kentucky ophthalmologist Dr. Jayakrishna Ambati, has discovered a molecular mechanism implicated in geographic atrophy, the major cause of untreatable blindness in the industrialized world. ... Concurrent with this discovery, Ambati's laboratory developed two promising therapies for the prevention of the condition. ... Geographic atrophy, a condition causing the death of cells in the retina, occurs in the later stages of the 'dry type' of macular degeneration, a disease affecting some 10 million older Americans and causing blindness in over 1 million. There is currently no effective treatment for geographic atrophy, as its cause is unknown. Ambati's team discovered that an accumulation of a toxic type of RNA, called Alu RNA, causes retinal cells to die in patients with geographic atrophy. In a healthy eye, a 'Dicer' enzyme degrades the Alu RNA particles. ... We discovered that in patients with geographic atrophy, there is a dramatic reduction of the Dicer enzyme in the retina. When the levels of Dicer decline, the control system is short-circuited and too much Alu RNA accumulates. This leads to death of the retina. ... Alu elements make up a surprisingly large portion - about 11 percent by weight - of the human genome, comprising more than 1 million sequences. However, their function has been unknown, so they have been called 'junk' DNA or part of the 'dark' genome. The discovery of Alu's toxicity and its control by Dicer should prove of great interest to other researchers in the biological sciences ... Ambati's team developed two potential therapies aimed at preventing geographic atrophy and demonstrated the efficacy of both approaches using laboratory models. The first involves increasing Dicer levels in the retina by 'over-expressing' the enzyme. The second involves blocking Alu RNA using an 'anti-sense' drug that binds and degrades this toxic substance. ... Ambati's group is preparing to start clinical trials by the end of this year."

Link: http://www.eurekalert.org/pub_releases/2011-02/uok-pdi020311.php

What is your proteome? In short, it is the list of all the proteins built within your body and their abundance - a parts catalog for your biological machinery. Analysis of even modest fractions of the proteome has only recently become practical, but it is potentially a good way to measure the complexity of repairing and reversing aging, or gain insight into which contributing mechanisms of aging are the most important. Aging is no more than change: damaged proteins, unwanted molecules, things in the wrong place at the molecular level - which leads to malfunction and failure in the large-scale organs and processes of the body.

The good news for today is that a comparison of young and old proteomes in mice shows that there is little change with aging. This is a positive result for the future of longevity science, because it means researchers can rapidly follow up on the few changes that were identified. The opposite result - many changes, as is the case for gene expression - would have been rather discouraging: a sign that matters are very complex in yet another area of the biology of aging, and that much work would have to take place in order to understand the relevance of the data.

From the open access paper (for the full paper, you'll want the PDF version):

The biological process of aging is believed to be the result of an accumulation of cellular damage to biomolecules. While there are numerous studies addressing mutation frequencies, morphological or transcriptional changes in aging mammalian tissues, few have measured global changes at the protein level. Here, we present an in depth proteomic analysis of three brain regions as well as heart and kidney in mice aged 5 or 26 months.

...

In frontal cortex and hippocampal regions of the brain, more than 4,200 proteins were quantitatively compared between age groups. Proteome differences between individual mice were observable within and between age groups. However, mean protein abundance changes of more than two-fold between young and old mice were detected in less than 1% of all proteins and very few of these were statistically significant. Similar outcomes were obtained when comparing cerebellum, heart and kidney between age groups. Thus, unexpectedly, our results indicate that aging-related effects on the tissue proteome composition at the bulk level are only minor and that protein homeostasis remains functional up to a relatively high age.

It is unexpected, given the gene expression findings to date - but welcome. I look forward to seeing the results from human studies. Given the free-falling cost of bioinformatics, and commensurate improvement in the technology, comparing proteomes in young and old people will be a graduate student project within a handful of years.