It's not just the genes, but it's not just the environment, either

Damien: Dr. L. Stephen Coles, M.D., Ph.D., Co-Founder of the Los Angeles Gerontology Research Group, commented today on a recent paper by the researcher Joao Pedro de Magalhaes and his colleagues, quoted below. Some of this response is compressed and technical, but I think it gives a good sense of the way in which exploratory science is beginning to unpick the locks of aging—and perhaps eventually to find a way around it by controlling the epigenetic aspects of cell growth and maintence.

Epigenetics is the cell’s control process switching on or off, or up or down, the activities of each gene. To quote the definition by Ali Shilatifard, Ph.D.: “an epigenetic trait is a stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequence.” As Science Daily amplifies this: “Shilatifard and colleagues have also proposed three categories of signals that operate in the establishment of a stably heritable epigenetic state. The first is a signal from the environment, the second is a responding signal in the cell that specifies the affected chromosomal location, and the third is a sustaining signal that perpetuates the chromatin change in subsequent generations.”

Dr. Coles cites Joao Pedro de Magalhaes’s paper on the genetics of aging in model organisms [1], and comments:

I believe that it provides us with a proper vision for the relation of genomics with epigenetics (Section D). I believe that it is futile to tease out the networks of gene interactions without epigenetic changes as a function of age. Epigenetics (nRNAi) is hidden in the non-coding portion of the DNA. Gene expression profiles of senescent cells are being worked out by Judy Campisi at the Buck Institute and by others. Cells with the senescent phenotype send out cytokine signals to adjacent cells in a positive-feedback loop that causes whole tissues to shut down with age, as they still take up space and consume caloric resources (oxygen and nutrients) without performing their important biological function(s). (And all of this as a defense mechanism against cancer?) Think of the heterochronic/parabiosis experiments with mice. We need to identify the cytokine network that triggers this senescent phenotype. Wellness depends on having cells that function in the manner that they did when we were young and constantly growing. The link of the genome to the onset of puberty will be a key step in this direction, since I believe it is under tight regulatory/programmatic control in the SCN (Supra Chiasmatic Nucleus); preparing to indulge in sex is the beginning of the process of senescence, in the sense of cellular turnover slows (fresh cells not keeping up with cell loss -- the Second Law of Thermodynamics [Entropy]) in which desynchronization of clocks and mitochondrial ROS take over with a net loss of vitality (fitness) as one passes through menopause/andropause and the genomic code runs out of new instructions (the pretty flower wilts, as it were). If this process is all programmed differently in different species then it is possible to contemplate reprogramming our own genomes (with artificial chromosomes) to suit our own personal agenda, as opposed to the uninspired stochastic Darwinian Agenda handed to us by Nature without our consent. Can we accept Her compelling us to become the prisoners of frail, blind, deaf, senile, and emaciated bodies just because we were tapped to enter into Her capricious n-person game? Homo sapiens are now at a stage in which we have figured out how avoid being consumed by other creatures/predators who would seek to eat us for lunch (that took a few hundred thousand years). But our present human condition still remains as Shakespeare poetically phrased it in Macbeth (Scene V)...  

Tomorrow, and tomorrow, and tomorrow

Creeps in this petty pace from day to day

To the last syllable of recorded time;

And all our yesterdays have lighted fools

The way to dusty death. Out, out, brief candle!

Life's but a walking shadow, a poor player

That struts and frets his hour upon the stage

And then is heard no more. It is a tale

Told by an idiot, full of sound and fury,

Signifying nothing.

Not if we can engineer our way around it, it won't signify "nothing."      I put in a link on the grg.org website to your Table of the more than 20 companies worldwide that are focusing specifically on the aging process [2]. Also, thank you for your continuing to maintain the GenAge data base [3] of more than 700 genes that have been identified that regulate lifespan in model organisms across several metabolic pathways (TOR, SIR-2, SCH-9). This is a data base that I expect will expand considerably in the next five years, and we need to keep it up to date for our stem-cell research collaborators and our students.

 Refs. : 1. Joao Pedro de Magalhaes, et al, "Genome-Environment Interactions That Modulate Aging: Powerful Targets for Drug Discovery," Pharmacological Reviews, Vol. 64, No. 1, pp. 88-101 (2012).

2. http://whoswho.senescence.info/

3. http://genomics/senescence.info/genes/

Extreme Longevity

Damien: On a listserv of gerontology experts dedicated to studying extreme longevity (super-centenarians in particular, those who survive past the age of 110), this point was recently made:

In 1965, there are 5+ workers for every retiree. Today, there are 3.3

workers for every retiree.

The number of workers per retiree will drastically fall once all baby

boomers have retired. So, if we want a society in which longevity

increases and we want to maintain the same standard of living, then it

logically follows that a fundamental shift will need to happen.

This outcome, though, is obviously dependent on many other factors as well. For a start, some countries (Australia, for example) don't treat the aged pension as a right but as a safety net, like insurance, so if you're wealthy enough not to absolutely need it, you don't get it. That seems equable enough to me (I’m ineligible for an Aussie pension myself), but I can hear most people in the USA squealing with indignation if this fix were suggested. “We paid for it, and we want our entitlement!” Yes, true enough—but then you pay for your health insurance, too, and if you’re lucky enough not to get ill your contribution is shared among the less fortunate. And if you do fall sick, or suffer a bad accident, you’re surely glad you paid all those years.

In any event, people are living longer, way beyond the five or six years after retirement that used to be the norm when Social Security was introduced. But simply raising the age of retirement year after year, as healthy lifespan is increased by medical intervention, isn’t going to help, even though people will remain fit for longer. People can't compete with machines, especially smart machines. I discussed this impending crunch years ago in my book The Spike.

Barbara: The problem of fewer young workers to support a growing mass of old people implies that there is too much work to be done and not enough people to do the work. George Friedman addresses this in The Next Hundred Years, pointing out that this is already a problem in some European countries, such as Germany.  Thomas Bock was at my nephew’s wedding about a month ago and talked of research he and his students are doing on holistic optimization of buildings. This got me thinking about how nice it would be if my home could take care of cleaning itself, cleaning me, obtaining and preparing food, dispensing my medications. Based on my observations while taking care of my mother, my impression is that one of the main reasons old people end up in nursing homes is that they can’t handle some of the more important aspects of life, such as cleaning the house, cooking meals, caring for clothing, driving to the store for groceries. Not so very long ago, that list might have included growing or hunting food.

For most people, the cost of hiring a housekeeper, cook, nurse, driver, etc. is prohibitively expensive. Despite the relatively high unemployment numbers, there is a shortage of people willing to do housework at affordable rates. There are “undocumented” people who would love to have the jobs, but it’s a criminal offence to hire them (Friedman writes that in a few years, the U.S. will be begging people from Mexico to come here and work). So the only reasonable choice for most people is to go to a nursing home or assisted living facility.

If old people could retrofit their homes, or move to new apartments that do the cooking, cleaning, and shopping for them, then some of the people now working in nursing or assisted living homes would be out of work. Which is the second potential problem Damien mentioned: fewer jobs.

The first problem, fewer young people to support a growing population of old people, could be solved by machines to do most of the work. But this leads to the second problem: if machines do most of the work, there aren’t any jobs to go around. Note that Damien is not talking about stupid machines like vacuum cleaners that have to be pushed around by humans, or even robotic vacuum cleaners that run themselves and tuck themselves away out of sight when they’re done. He’s talking about machines that can practice law, cut your hair in the exact style you want, produce a perfect steak from an assortment of chemicals, compose music that will precisely fit your mood.

In a world where no one has a job (as we understand the concept), the problem of too few young people for each old person disappears. Which is not to say that too many old people would be a problem in the first place if the old people were healthy and able to work, rather than falling apart.

Most of the people I know run their own businesses and enjoy going to work each day. Many of them do not want to retire. They might have an “exit strategy” for the business they’re running right now, but in most cases, the last thing they plan to do is sit around letting young people support them. No, they want to start another business, or learn new skills.

President Obama will address the public on September 8 to talk about creating jobs. This is understandable, given the prevalent belief that a person must have a routine job, working for someone else or some large organization, in order to make a living. I used to think the same thing when I was young. In my mid-20s, when I was “between jobs,” fretting about being unemployed, my then-boyfriend said (not an exact quote, but this is the way I remember it), “You don’t need a job. You need a way to earn money. That’s two different things. There are ways to earn money other than getting a job.”

He listed a few of the possibilities: I had enough stuff lying around to open a second-hand shop; I had a degree in mathematics, so I could tutor students who were having trouble with math. I don’t remember any of his other suggestions, and I never ended up doing any of the things he suggested. But his confident statement that I did not need a job in order to earn money turned on a little light bulb in my mind and has made all the difference in my life. Thank you, Kim Marshall.

Staying Healthy for a Long, Long Time

Barbara: Professor Michael Rose at UC Irvine has written a provocative article for the latest issue of Cryonics Magazine.

He writes:

 I am not going to argue against cyberimmortality or cryo-immortality here.  After 
all, the value of back-up plans is self-evident.  Instead, what I am going to offer is an informal introduction to a third possibility.  This  possibility is one in which aging is stopped, and then repair and refurbishment are used to achieve immortality by the simple expedient of not dying in the first place.

Yeah, I always liked that Woody Allen quote about not wanting to achieve immortality through great works, but rather by not dying. A belief in physical immortality, or even living for, say, 200 years, might seem delusional. Rose would have thought so, as recently as three years ago, but no longer.

He became interested in the cessation of aging that occurs in animals toward the end of their life spans. Humans, he claims, stop aging at around age 100 (although other experts dispute this). Unfortunately, by the time they're that old, most people are in a pretty rotten condition. So Rose wondered if one might be able to halt the aging process at a younger age. Experiments with populations of fruit flies indicate that this is possible. In the last 30 years, Rose and his team have bred flies for longevity by choosing eggs only from the longest lived individuals--and his population of flies now live four times as long as ordinary wild flies.

Damien: So what's going on here? Rose used to believe that aging was the result of a trade-off between genes that promote health and vigor in youth but turn out to have bad consequences in later years. This notion was first advanced by evolutionary biologist George Williams more than half a century ago, but Professor Rose gave it the name used today: Antagonistic Pleiotropy. What's new and surprising, then, is that Rose no longer thinks Antagonistic Pleiotropy is a sufficient explanation for his robust ancient flies.

If he's right, changes in nutrition and lifestyle might allow people right now to maintain our current state of health indefinitely. That is, there'd be no clock relentlessly ticking away your fated lifespan, no necessary cumulative damage that dooms you to death. Mind you, Rose is not talking about rejuvenation. If you're 70, you'll stay that way--but you'll be the healthiest 70 year old it's possible to be, indefinitely. Rejuvenation might eventually be possible, using technology we don't yet possess (nanomachines in the bloodstream, say, to repair or remove damaged cells and keep organs as clean and fresh as an adolescent's), but we're nowhere near that yet. But Rose argues that we do already know how to halt aging. His company Genescient (co-founded by Dr. Cristina Rizza and physics professor and science fiction writer Gregory Benford) is making nutraceuticals (StemCell 100) designed with that in mind. Sooner or later, we'll know if it works.

Barbara: Rose's blog, Michael Rose's 55 is devoted to the possibilities of stopping the aging process of humans while we're still in good enough shape to enjoy life.