Science Magazine on Aging and the Path Towards Treatments

To go along with Nature Medicine's latest focus issue on aging and the prospects for producing therapies to treat aging, I see that Science Magazine's December 4th special issue covers much the same topic. It is interesting to see this example of a convergence of discussion in respected publications, representative of a greater willingness by the scientific community to earnestly consider and plan a path towards the medical control of aging.

I used the occasion of the Nature Medicine issue to complain about the present mainstream research focus; when it comes to aging, the majority of scientists involved in the field undertake research programs that cannot possible produce meaningful results in terms of additional years of healthy life. Meanwhile approaches that can in principle produce real, actual rejuvenation in old people, and prevent aging in the young, are neglected in comparison. Today I'll instead focus on the more positive side of things, which is that the treatment of aging is now a serious, accepted, legitimate field of research within the broader scientific community. It took twenty years of persuasion and slow bootstrapping of research results to get to this point, but now here we are.

Ten or fifteen years ago for scientists to talk in public about extending healthy human life spans was to risk funding and career, which certainly stunted the pace of progress. There has been a sea change in the last few years as the results of advocacy flourished - things couldn't be more different now. Within the extended research community the important arguments today are over how aging should be treated, not whether or not it is plausible, useful, or desirable. The common sense position has finally won out among scientists: aging should be treated because it is the cause of age-related disease, and it is a given that we should work towards curing and preventing age-related disease because it is a source of suffering, pain, and death. If you think that suffering, pain, and death are bad things, then you should be all for working as hard as possible to end degenerative aging. It is the greatest single cause of suffering, pain, and death in the world by a very broad margin: more than 100,000 lives lost every day, and hundreds of millions of others in various states of pain, frailty, and disability.

Toward Healthy Aging, Putting Off the Inevitable

The dream of cheating death has evolved into a scientific quest to extend healthy life span. Scientists and doctors are looking for ways to maximize the number of years that we live free of chronic diseases, cancer, and cognitive decline. But before we can intervene, we have to understand the cellular and molecular mechanisms that drive aging and senescence. Some clues reside in our telomeres, the tips of our chromosomes that shrink with age. Others lie in our stem cells, which can only go on for so long repairing our tissues. Our mitochondria, too, the so-called powerhouses of the cell, may hold some answers to prolonging youthfulness. Other research points to changes in the gut microbiota associated with frailty in the aged. At a mechanistic level, the modulation of coenzyme NAD+ usage or production can prolong both health span and life span. Current geroscience initiatives aim to harness basic insights in aging research to promote general advances in healthy aging.

Questions remain throughout the aging field. By tweaking everything from genes to diets to environmental temperature and mating, scientists have created Methuselah flies and other remarkably long-lived animals while garnering fundamental insights into the biology of aging. Still, researchers puzzle over the most basic questions, such as what determines the life spans of animals. Meanwhile, a handful of molecular biologists are searching for ways to measure a person's biological, as opposed to chronological, age, but that quest, too, has proved elusive. An ever-growing literature addresses both theoretical and pragmatic approaches to the challenge of aging. In this special issue, we have focused mainly on the cellular aspects of mammalian aging, with the goal of spurring future developments in promoting health span, if not life span.

Death-defying experiments

The longest lived laboratory animals shed light on the forces that lead some to any early grave and others to beat the odds and see many more birthdays than the norm. Experiments with mice, flies, and worms have won that manipulating genes, restricting calorie intake, and giving animals drugs can extend life span - by as much as 10-fold. Researchers also have elucidated several biochemical pathways that lead to longevity. And one lab animal, the hydra, appears to have found a fountain of youth of sorts: Unless it sexually reproduces, it appears immortal.

Stem cells and healthy aging

Research into stem cells and aging aims to understand how stem cells maintain tissue health, what mechanisms ultimately lead to decline in stem cell function with age, and how the regenerative capacity of somatic stem cells can be enhanced to promote healthy aging. Here, we explore the effects of aging on stem cells in different tissues. Recent research has focused on the ways that genetic mutations, epigenetic changes, and the extrinsic environmental milieu influence stem cell functionality over time. We describe each of these three factors, the ways in which they interact, and how these interactions decrease stem cell health over time. We are optimistic that a better understanding of these changes will uncover potential strategies to enhance stem cell function and increase tissue resiliency into old age.

Healthy aging: The ultimate preventative medicine

Age is the greatest risk factor for nearly every major cause of mortality in developed nations. Despite this, most biomedical research focuses on individual disease processes without much consideration for the relationships between aging and disease. Recent discoveries in the field of geroscience, which aims to explain biological mechanisms of aging, have provided insights into molecular processes that underlie biological aging and, perhaps more importantly, potential interventions to delay aging and promote healthy longevity. Here we describe some of these advances, along with efforts to move geroscience from the bench to the clinic. We also propose that greater emphasis should be placed on research into basic aging processes, because interventions that slow aging will have a greater effect on quality of life compared with disease-specific approaches.

Hi Everyone,

In the " Death-defying experiments", editor mentioned the GHR-KO mice can live two fold than the wild type mice. And the researchers discovered that in 2003. That was really shock !
So far, we can not get more information about this GHR-KO 11C mice.

What is the specific gene knockout in the mice ?
How about the other biological phenotypes during aging ?
We only can find few academic papers related with this GHR-KO 11C mice.

It was more than 10 years. They must have some advancement in understanding aging processes as well as anti-aging interventions.

Just look forward to the breakthrough news in anti-aging research and intervention.

Posted by: Stan Chen at December 10th, 2015 10:52 PM

@Stan Chen: A search for "GHR-KO" in this site gives several recent articles.

Posted by: Antonio at December 11th, 2015 3:44 AM


Sure there are several papers related with "GHR-Ko"(49 papers) or "GHR-Aging" (108 papers) when we searched on NCBI.
However, you can find 2800 papers related "IGF-Aging".

The varous mouse models manipulating IGF signaling only can prolong 20~30% lifespan, but GHR KO mice showed 2 fold long lifespan.
Why the academic papers related with GHR-Aging are relative few?

Posted by: Stan Chen at December 11th, 2015 7:45 AM

@Stan Chen

Hi Stan ! It's also something that puzzles me. I am guessing GHRKO mouse is not the most popular mouse model.
And whatever that's been discovered in it is done and there doesn't seem much more to discover beyond what this model does (reaching a results limit ?). I believe, also, the reason there is 20 times more papers on IGF is because it is a 'large primary pathway' (vague) that touches so many other connected pathways, and pathways are studied in many different species at the same time, that all share the same evolutionary conserved IGF pathway; hence the much higher number of IGF studies (in mouse, fly, worms, yeast, cat, dog, rat, cow, pig, killifish, etc). This also allows comparative research between these species IGF pathway effects, whereas GHRKO effect is more precise studies to the mouse. Also, when it touches specifically growth, growth hormones, endocrinal systems, you pretty much step out of general biology but enter endocrinal biology specificity; many studies don't even talk about Hormones, yet they go on about IGF, ...yet they are inter-linked, it's like you can't talk about IGF without talking hormones and growth (since it's i-'G'-f...Growth). This is also the more 'sexual' part, hormones touch the sexual hormones, sexual organs, sexual reproduction, sexual maturation (puberty), see it's getting too specific for these regular studies seeing 'less IGF in GHRKO mouse and Ames/Snell dwarf'...Ok. So what, I mean I can show you people who have more IGF and live longer...I spoke in other messages about weak translatability, IGF is a very conserved thing in humans and does not share the same effects as in mouse - because of different specie evolutionnary context. What can be good in mouse is quite not that good or no effect at all in human. I recently mentioned of centenarians who are dwarfs and have low IGF in their bloodstream, but I also mentioned centenarians who are actually quite tall and have *more* IGF and also more Brain Mass. IGF is necessary for brain retention (see my previous comments), neurogenesis and brain cellular reorganization/remodeling (tissue ECM plasticity). Just my opinion but these super long lived GHRKO and Ames/Snell/CR starved-to-death mice that live nearly 3 to 5 years long are not translatable in human (perhaps this is about as close to a dwarf centenarian human comparison...even said, most centenarians are not so small either, you must keep your bone ossature and skeletal muscle mass (bone loss..what controls bone minerality/growth...and stopping muscle wastage and sarcopenia of old age to build muscle mass ? IGF.). Ames/Snell and other GH ko mouse are sterile and can't have children, of course their sexual GH are gone, their pituitary, testicular, ovary and thyroidal hormones are none. They are alike Barren centenarians; yet many centenarians; including dwarfs or tall ones (some centenarian male were 5'10'' that is incredible bone retention and some Japanese centenarians have higher Testosterone and a Healthy Sexual life at a 100..yes!) have had childre. The sexual energy resource cost (sexual genes) vs longevity (longevity genes) can genetically (re)balanced to maintain adequately low chlidren offspring output (low sexual resource cost), not sterile, while gaining a very long life (resource use for damage reparation/cell maintenance); as these centenarians show. One of the best trick of evolution is Neoteny/Juvenilization (late puberty, centenarians are almost always late puberty/sexual maturation people (if it came soon your chance to become centenarian not so good). Meaning retarding growth is Good, and there can be a middle ground where sex/offspring happens much later and this gives one a possibility of long life. But in humans, body retention is very important (bone morphogenesis, muscle retention, not osteoporosis, sarcopenia, frailty. etc, so IGF and growth balance is needed; much less so in mice who live barely 5 years, so who cares for them; its a 'live quick model' by evolution for them; we have 'long life' model so we need to mainain our body and brain; that's where IGF/HGH)

Posted by: CANanonymity at December 11th, 2015 2:22 PM

'' The naked mole rat's brain contains unusually high levels of NRG-1, a neuroprotecting protein, which preserves high activity, ***bone health***,
and *cognitive ability* throughout its lifespan, new research shows. And because the rodent has an 85 percent genetic similarity to humans, continuing investigation could lead to a longer and healthier life for us. ''

The neotenous (late puberty) naked mole rat lives up to 35 years old (it makes mice look real bad in terms of lifespan potential and is much closer model to us) and maintains Bone Health via brain Neuregulin-1 NRG-1, NRG-1 acts in concert with IGF-1 receptors (crosstalk), for brain IGF-1 controls bone health/growth, with NRG-1. Naked mole rats are much more in line with what is going in us on the subject of IGF/GFs/GHs. Their results show that to live beyond a 5 year mouse, 35 year old us naked mole rat, must 'spread-the-growing-late' (puberty) over a long period to maintain body in a state of low low latent 'continous/constant' slow growth/cell reorganization (slow plasticizing tissue) and then reach sexually capable adult age.

'' We find that *IGF-I, like NRG-1,* can prevent the apoptotic death of postnatal rat Schwann cells cultured under conditions of serum withdrawal. ''

This means crosstalk and IGF and GFs/GHs are extremely important, just like NRG-1 is for brain neuron regulation.


Posted by: CANanonymity at December 11th, 2015 3:00 PM

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