Fight Aging!

Resilient Biochemistry in Naked-Mole Rats

Naked mole-rats are becoming very well studied. Researchers are attempting to find the root causes of cancer immunity and exceptional longevity in this species, with an eye to creating beneficial medical biotechnologies for humans. Fight Aging! has seen a couple of items on naked mole-rats already this month, which is illustrative of the present pace:

Present theories are varied, but on the longevity side of the house the consensus appears to lean towards an increased resistance to forms of cellular membrane damage - naked mole rat membranes are built of a more resilient mix of proteins than those of comparable species. This is known as the membrane pacemaker hypothesis of aging:

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. ... Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

Continuing the naked mole-rat theme for May, here is another just-published open access paper on the resilience of naked mole-rat biology (abstract, and full article):

Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ∼8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to [cancer] but also shows minimal decline in age-associated physiological traits.
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Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing [median lethal dose] values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins.

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Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process.

You might also look back a few years at other research into the role of Nrf2 in determining species longevity. The details can be a little overwhelming, but the big picture remains one of damage at the level of cells and protein machinery: less damage and more resilience to damage means a longer life span.

Arguing a Role for the Hypothalamus in Aging

Researchers here analyze the proteome of the hypothalamus and argue for an important role in coordinating bodily responses to ongoing changes caused by aging: "The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. ... Based upon our rigorous analyses, we show that endogenous physiological responses to aging may be strongly orchestrated by the expression level of the GIT2 protein. The relevance of the hypothalamic expression level of this protein to the aging process in both neuronal and energy-controlling tissues reinforces the importance of this organ in the potential future development of targeted pharmacotherapeutics designed to interdict a multitude of age-related disorders."

Link: http://dx.doi.org/10.1371/journal.pone.0036975

S1P and Stimulation of Muscle Satellite Cells

A possible method of boosting muscle repair, and thus treating muscle wasting conditions - such as the sarcopenia that attends aging: "a lipid signaling molecule called sphingosine-1-phosphate or 'S1P' can trigger an inflammatory response that stimulates the muscle stem cells to proliferate and assist in muscle repair. ... mdx mice, which have a disease similar to Duchenne Muscular Dystrophy, exhibit a deficiency of S1P, [and] boosting their S1P levels improves muscle regeneration ... The ability of muscles to regenerate themselves is attributed to the presence of a form of adult stem cells called 'satellite cells' that are essential for muscle repair. Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated. However, after muscle injury, these stem cells 'wake up' through unclear mechanisms and fuse with the injured muscle, stimulating a complicated process that results in the rebuilding of a healthy muscle fiber. S1P is a lipid signaling molecule that controls the movement and proliferation of many human cell types. ... S1P is able to 'wake up' the stem cells at the time of injury. It involves the ability of S1P to activate S1P receptor 2, one of its five cell surface receptors, leading to downstream activation of an inflammatory pathway controlled by a transcription factor called STAT3. [This results] in changes in gene expression that cause the satellite cell to leave its 'sleeping' state and start to proliferate and assist in muscle repair. ... If these findings are also found to be true in humans with Duchenne Muscular Dystrophy, it may be possible to use similar approaches to boost S1P levels in order to improve satellite cell function and muscle regeneration in patients with the disease. Drugs that block S1P metabolism and boost S1P levels are now being tested for the treatment of other human diseases including rheumatoid arthritis. If these studies prove to be relevant in Duchenne patients, it may be possible to use the same drugs to improve muscle regeneration in these patients. Alternatively, new agents that can specifically activate S1P receptor 2 could also be beneficial in recruiting satellite cells and improving muscle regeneration in muscular dystrophy and potentially other diseases of muscle."

Link: http://www.sciencedaily.com/releases/2012/05/120515070307.htm

More Health, Longevity, and Medical Cost Data from the Ohsaki Cohort Study

You might recall that late last year I pointed out a large Japanese longitudinal study on incidental moderate exercise and lifetime medical costs:

The authors followed up 27,738 participants aged 40-79 years and prospectively collected data on their medical expenditure and survival covering a 13-year-period. ... The present results indicate that the multiadjusted lifetime medical expenditure from the age of 40 years for those who walked ≥1 h per day was significantly lower by 7.6% in men and non-significantly lower by 2.7% in women than for those who walked <1 h per day. This decrease in lifetime medical expenditure was observed in spite of a longer life expectancy (1.38 years for men and 1.16 years for women) among those who walked ≥1 h per day.

In another, more open access recent paper, the same authors have crunched the numbers for variations in weight among study participants. The story is much the same, as one would expect:

Although four previous studies have examined the association between obesity and lifetime medical expenditure, the results were inconsistent. ... We therefore conducted a 13-year prospective observation of 41,965 Japanese adults aged 40-79 years living in the community, which accrued 392,860 person-years. We examined the association between BMI and lifetime medical expenditure, based on individual medical expenditure and life table analysis. We collected data for survival and all medical care utilisation and costs, excluding home care services provided home health aides, nursing home care and preventive health services in participants of this cohort study.
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In spite of their short life expectancy, obese men and women had approximately 14.7% and 21.6% higher lifetime medical expenditure in comparison with normal weight participants, respectively.

Don't get fat, don't stay fat, and don't be a couch potato. Thus speaks the weight of evidence - but then we all knew that, right? Being unhealthy has definitive material costs in the long term: years of life shaved off, the rot of your body and mind, and the monetary cost of medical services you would otherwise not have needed. There are plenty of people in this world, far too many, who don't presently have the luxury of choice when it comes to being healthy: the genetically impaired, the immune-damaged, the infected, the wounded. Why fritter away your choice for the sake of eating and laziness? It is almost a gesture of contempt.

A Popular Press Article on Longevity Science

The media and public at large have been trained to think of medicine, and especially longevity-related medicine, in terms of pills - things you can consume, colorful drug capsules produced in the old-style fashion by Big Pharma. This is somewhat ridiculous, and leads to a focus on the entirely the wrong branches of research, those unlikely to deliver meaningful healthy life extension. The future of rejuvenation biotechnology involves gene therapies, infusions of bacterial enzymes, and so forth; for the foreseeable future little of that will be stuff that you stick into your mouth. Calling these medicines drugs rather than procedures cheapens the complexity of what is being designed and developed. Nonetheless, the oral fixation in regard to public perceptions of medicine continues, fed by the lazy press and the self-interested supplement industry. Here is an example of that sort of headlining: "But imagine if there were a drug that would slow down the aging process itself, a drug that didn't just treat a single disease but instead targeted multiple diseases of old age at once? It may sound far-fetched, but that's precisely what longevity scientists are working hard to produce. ... It's not just that we're trying to make people live longer; we're trying to make people live healthier. This is an exciting time for research. ... Indeed, top-notch research labs are rolling out studies at a rapid rate, and a growing chorus of experts believe the advances being made will ultimately lead to a crop of drugs capable of extending healthy lifespans. Signs of progress are abundant in medical journals. ... [researchers] published results showing they could markedly delay the onset of age-related diseases in mice by killing off the rodents' senescent cells. Senescent cells have stopped dividing and accumulate as organisms age. Though seemingly dormant, they're not: Just as old cars in junkyards can leak oil for years, they emit harmful substances that appear to fuel many of the diseases that strike older people. ... And it's not just senescence research that is stoking excitement. Another team of scientists [has] managed to control the aging process by targeting specialized structures at the tips of chromosomes called telomeres. ... Other scientists have found that feeding aging mice rapamycin - an immunosuppressant that's used to prevent organ rejection after transplants - can extend the lifespan of mice significantly."

Link: http://health.usnews.com/health-news/articles/2012/05/14/the-hunt-for-an-anti-aging-pill-is-on