生物谷報道：傳統(tǒng)的觀念認為素食者,，或低熱量飲食具有保健長壽，防衰老的功能,。 小鼠,，大鼠，蠕蟲,，蒼蠅和酵母能夠在低熱量飲食下存活很久,，這也是哺乳動物抵抗癌癥和其它與年齡相關疾病的方式。這些自然現(xiàn)象早已被觀察到或證實,，但是其中機理并不是很清楚,，近幾年來，這一領域有了突破性進展,。
去年生物谷內有一篇類似報道：熱量和衰老之間的聯(lián)系,，認為與某些基因有關。Science以前也有文章認為熱量過多,，會導致自由基產(chǎn)生過多,，從而攻擊線粒體等亞細胞結構，導致衰老,，如Science:線粒體突變的積累可能加速衰老 ,，印證了高熱量與衰老的關系,。早在2003年，Nature》:哺乳動物限制熱量攝入可更長壽,，被認為是2003年科學的最重大的發(fā)現(xiàn)之一,，去年Nature上報道Nature:未來的糖尿病藥物可能靶向新的蛋白質反應，也從側面反應了衰老與熱量的關系,。這一系列的發(fā)現(xiàn)都證實了,，熱量與衰老之間確存在必然聯(lián)系，然而到底是基因水平的聯(lián)系,，還是以往的自由基學說為主呢,？
上周Science一篇新的文章，從基因角度研究這一課題,，發(fā)現(xiàn)了一個長壽基因家族,，并命名為SIR2基因，認為與此有關?，F(xiàn)在,，哈佛大學醫(yī)學院和 UC Davis 的科學家們發(fā)現(xiàn)了四個SIR2 的家族基因，它們同樣能夠延長壽命,，表明整個SIR2家族基因都與控制壽命有關,。這項研究為研發(fā)新的延長壽命和抵抗年齡相關疾病的藥物提供了幫助。
同樣,，這一研究再次證實了SIR2家族的基因與衰老之間的密切聯(lián)系,，這使衰老的研究會出現(xiàn)突破性進展。同時也會帶來抗衰老藥物的研究的突破,。如傳統(tǒng)的抗衰老藥物白藜蘆醇的最新研究進展,，已被證實確能提高該基因的活性。有理由相信,，這一領域會在今后一段時間內有快速發(fā)展,。
相關文章：
·衰老機理的學說
·《Nature》:哺乳動物限制熱量攝入可更長壽
·研究人員發(fā)現(xiàn)能保護基因組穩(wěn)定性的酶
·白藜蘆醇的最新研究進展
·哺乳動物限制卡路里攝入可更長壽
·生命周期的決定論文集
·PML調節(jié)轉錄
·研究發(fā)現(xiàn)一種能延長壽命的蛋白
·《Nature》:不用節(jié)食能否延長壽命
·研究發(fā)現(xiàn)扭轉衰老過程的關鍵
·研究發(fā)現(xiàn)驅使細胞衰老的分子機制
·科學家揭示關于衰老的“綠色理論”-
·基因組完整性與衰老之間的關系
·《Sceince》:了解衰老的各個方面
·《Nature》:衰老從40歲開始
·Johns Hopkins發(fā)現(xiàn)過早衰老與基因缺陷有關
·基因研究又有新突破 生命衰老與X染色體有關
·Science:線粒體突變的積累可能加速衰老
·《任小二快報》:未老先衰-衰老的線粒體學說
·《Sceince》:用猴子模式研究人類衰老
·Sir2 Protein: An Important Link in Aging and Metabolism
Science上文章相關的鏈接
Lamming DW, Latorre-Esteves M, Medvedik O, Wong SN, Tsang FA, Wang C, Lin SJ, Sinclair DA. HST2 Mediates SIR2-Independent Life-Span Extension by Calorie Restriction. Science. 2005 Jul 28
最新有關SIR2基因研究進展，并附全文下載
Hisahara S, Chiba S, Matsumoto H, Horio Y. Transcriptional Regulation of Neuronal Genes and Its Effect on Neural Functions: NAD-Dependent Histone Deacetylase SIRT1 (Sir2alpha).
J Pharmacol Sci. 2005 Jul;98(3):200-4. Epub 2005 Jul 9. [PDF (143K)]
Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev. 2005 Jul 1;19(13):1544-55. [PDF]
Lemieux ME, Yang X, Jardine K, He X, Jacobsen KX, Staines WA, Harper ME, McBurney MW. The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals. Mech Ageing Dev. 2005 Jun 15; [PDF]
Tamburini BA, Tyler JK. Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair. Mol Cell Biol. 2005 Jun;25(12):4903-13.
Michel AH, Kornmann B, Dubrana K, Shore D. Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing. Genes Dev. 2005 May 15;19(10):1199-210. [PDF]
SIR2基因及蛋白相關信息：
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=851520
Gene type: protein coding
Gene name: SIR2
RefSeq status: Reviewed
Organism: Saccharomyces cerevisiae (strain: S288C)
Lineage: Eukaryota; Fungi; Ascomycota; Saccharomycotina; Saccharomycetes; Saccharomycetales; Saccharomycetaceae; Saccharomyces
Gene aliases: MAR1
有關衰老的一般知識與問答（英文）
What is Aging?
Loss of structure and function in aging.
Figures represent percentage of a given function remaining in an average 75-year-old man compared with that found in an average 30-year-old man, the latter value taken as 100%.
Weight of brain 56%
Blood supply to brain 80
Output of heart at rest 70
Number of glomeruli in kidney 56
Glomerular filtration rate 69
Speed of return to normal pH of blood after displacement 17
Number of taste buds 36
Vital capacity 56
Strength of hand grip 55
Maximum O2 uptake during exercise 40
Number of axons in spinal nerve 63
Velocity of nerve impulse 90
Body weight 88
Aging is the progressive loss of physiological functions that increases the probability of death.
This table gives some data.
The decline in function certainly occurs within cells. This is especially true of cells that are no longer in the cell cycle:
neurons in the brain; skeletal and cardiac muscle; kidney cells.
Tissue and organs made of cells that are replenished by mitosis throughout life. e.g.,
blood intestinal epithelium
show far fewer signs of aging.
Do all Creatures Age?
At the start of the 20th century, infectious diseases such as pneumonia and influenza caused more deaths in the United States than "organic" diseases like cancer. Now the situation is reversed. The availability of effective weapons against infectious disease, e.g., antibiotics and immunization, has greatly increased the average life span (but not maximum life span) and resulted in "organic" diseases like cardiovascular disease and cancer becoming the most common cause of death.
No. Very few organisms — and virtually no animals — show signs of aging. Random mortality from
starvation predation infectious disease a harsh environment (e.g., cold)
kills off most animals long before they begin to show signs of aging.
In fact, only humans and the animals they choose to protect (pet dogs, cats, parrots, etc.) age.
And even for humans, aging has only become common in recent decades. In 1900, a newborn child in the U.S. could look forward to an average life expectancy of only 49 years. Infectious diseases were the major causes of death, killing most people before they reached an age when aging set in.
Three-quarters of a century later, life expectancy had risen to 73 years and "organic" diseases, including all the diseases of aging, had replaced infectious diseases as the major cause of death. Today, the life expectancy has risen to 80 for women (74 for men), and coping with an aging population has become a major economic and social challenge in the U.S. [Link]
The graph at right shows four representative survival curves. The vertical axis represents the fraction of survivors at each age (on the horizontal axis).
Curve A is characteristic of organisms that have low mortality until late in life. Then mortality increasingly becomes the endpoint of the aging process. Curve B is typical of populations in which such environmental factors as starvation and disease obscure the effects of aging (and infant mortality in high). Curve C is a theoretical curve for organisms for which the chance of death is equal at all ages. This might be the case for organisms that show few, if any, signs of aging (some fishes) or those (e.g., songbirds in the wild) that suffer severe random mortality from environmental causes throughout life. Curve D is typical of organisms, oysters for example, that produce huge numbers of offspring accompanied by high rates of infant mortality.
Organisms with survivorship curves between C and D have no opportunity to show the signs of aging.
Aging in Invertebrates
Invertebrate animals have provided some important clues about the aging process.
Colonial invertebrates like sponges and corals don't show signs of aging. Even individual cnidarians, like the sea anemone that lived for 78 years, show little or no sign of aging. In all these cases, this is probably because there is constant replacement of old cells by new ones as the years go by. Lobsters also can live to a very old age with no obvious sign of a decline in fecundity or any other physiological process. But lobsters never stop growing, so once again it may be the continuous formation of new cells that keeps the animal going. In culture vessels, Drosophila does have a limited life span and shows signs of aging before it dies. Two factors have been found to influence the aging process and thus life span:
calorie restriction, that is, a semi-starvation diet. In fact, restricting food intake has been shown to increase life span (and slow aging) in all animals — including mammals — that have been tested. [More] Single genes have been identified that extend life span in Drosophila (and also in the invertebrate Caenorhabditis elegans).
Aging in Vertebrates
Some cold-blooded vertebrates:
fishes; amphibians; reptiles
have long life spans if they can survive environmental hazards (some tortoises are known to have reached 150 years of age).
In every case, these animals have no fixed size but continue to grow throughout life. This, of course, requires a constant supply of new cells, and this may be their secret.
The situation is different for the warm-blooded vertebrates, the birds and mammals.
They do have a fixed adult size and, if protected from environmental hazards, will show signs of aging.
Why Do We Age?
1. Programmed in our genes?
The pros
Single genes have been found that increase life span in Drosophila, C. elegans, yeast, and mice. [Link to discussion of the Igf-1 receptor in mice] Long life spans clearly run in human families. Aging often appears sooner in animals that suffer high death rates from external causes (e.g. predation) early in life.
Why should this be? Three (interrelated) possibilities:
The accumulation of harmful mutations (in the germline). Few individuals survive long enough for these to be selected against. Antagonistic pleiotropy. Genes that promote survival early in life at the expense of maintaining the body will be selected for.
So far, p53 is the best candidate. By forcing cells with damaged DNA to
stop dividing or even to die by apoptosis
it protects the organism from the threat of those cells becoming cancerous but at the expense of reducing cell renewal (e.g., by decreasing the size of the pools of stem cells). Disposable soma. Early death from external causes will select for genes that increase the chances of passing germplasm on (i.e. reproduction) at the expense of genes that might delay aging.
There is no way that natural selection can select for genes whose only beneficial effect appears after the age of reproduction is over. But
any genes that extend the reproductive period or any genes that promote fitness in youth as well as longevity
would be selected for.
The cons
High early mortality from external causes (e.g. predators) has been linked to early aging (in the survivors) in some animals, but the reverse has been found in others.
These contradictory results do not negate the role of genes in aging, but indicate that other environmental factors (e.g. more food left for the survivors) may skew the outcome.
2. The Inevitable Consequence of an Active Life?
The pros
Many cold-blooded vertebrates (e.g., many fishes and reptiles) do not show signs of aging. The effects of Calorie Restriction (CR).
The life span of yeast, C. elegans, Drosophila, birds, and mammals (mice, rats, and probably monkeys) can be extended, and signs of aging delayed, if they are maintained on a semi-starvation diet.
The increased life span of yeast subjected to calorie restriction requires a gene called SIR2 ("Silent Information Regulator 2"). SIR2 encodes the Sir2 deacetylase, an enzyme that removes acetyl groups from proteins. Increasing the activity of Sir2 extends the life span of yeast, C. elegans, and Drosophila.
It might seem unlikely that we could learn anything about longevity in mammals from studying yeast. But it turns out that mammals have a gene similar to SIR2 (called Sirt1 in mice).
Resveratrol, a small molecule found in red wine, activates the Sir2 enzyme and extends life span in yeast. It may do the same in Drosophila and C. elegans. In human cells, resveratrol activates Sirt1 mimicking the effects of calorie restriction.
Calorie restriction in mice and rats causes
the level of circulating insulin and insulin-like growth factor-1 (Igf-1) to drop; the level of NADH (produced by cellular respiration) within cells to drop; the production of the Sirt1 protein to increase markedly; apoptosis of cells to be inhibited; formation of adipose tissue to be suppressed; fats within already-existing fat cells to be hydrolyzed and their fatty acids secreted.
Monkeys on a calorie restriction diet show several metabolic changes, such as
lower body temperature; lower levels of insulin; higher levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS);
that are also associated with increased longevity in human males.
Why should calorie restriction delay aging?
No one knows for certain, but perhaps
it is because reducing calorie intake reduces female fecundity (at least in C. elegans, Drosophila, rats and mice). The energy that would have been devoted to producing offspring can be devoted instead to tissue repair and maintenance. reducing the intake of calories reduces metabolism. Why should a high metabolic rate lead to accelerated aging?
The Free Radical Theory of Aging
A major aspect of metabolism is the oxidation of foodstuffs by the mitochondria [Link]. Electron transport in the mitochondria generates reactive oxygen species ("ROS") such as
the superoxide anion (O2-), which generates hydrogen peroxide (H2O2)
Link to discussion of reactive oxygen species.
Although cells contain enzymes for detoxifying these reactive substances (e.g., catalase which breaks down H2O2), they eventually and inevitably damage macromolecules in the cell:
lipids Link to a discussion of the effect of ROS on lipids
proteins DNA
Damaged lipids and proteins accumulate in the cell, especially nondividing cells like
neurons heart muscle
producing an "aging pigment" called lipofuscin. (I am told that lipofuscin is also a principal component of ear wax.) Lipofuscin accumulates more slowly in the cells of animals on a calorie restricted diet.
But it may be damage to DNA that is the crucial factor in the decline in cell function with age. [Link]
In any case, transgenic mice containing the human gene for catalase (but with the targeting signal that would normally send the protein to peroxisomes replaced with that for mitochondria) live 20% longer than normal for their strain. [See Schriner, S. E. et al., Science, 24 June 2005]
The cons
Bats and mice are similar in size and metabolic rate, but bats can live ten times as long. Although glucose-starved yeast do live longer, they have an increased — not decreased — rate of cellular respiration. A higher metabolic rate is also seen with some procedures that greatly extend the life span of C. elegans. The beneficial effects of CR take hold at any time, at least in Drosophila. Even after three weeks on a rich diet (in the second half of the normal life span of adult flies), switching to a CR diet reduces mortality to the same degree as flies maintained on CR throughout their adult lives. The reverse is also true — switching from a CR diet to a rich diet quickly undoes the good work of the former. These results suggest that if a rich diet does produce irreversible and accumulating damage, its harmful effects on life span can be blunted at any time.
3. The Accumulation of Senescent Cells?
One might expect that cells removed from a mouse or human and placed in tissue culture could be cultured indefinitely just as bacteria can. But that is not the case.
When human fibroblasts, for example, are placed in culture, they proliferate at first, but eventually a time comes when their rate of mitosis slows and finally stops. The cells continue to live for a while, but cannot pass from G1 to the S phase of the cell cycle. This phenomenon is called replicative senescence. Fibroblasts taken from a young human pass through some 60–80 doublings before they reach replicative senescence.
Why should this be?
Cells — unless they retain the enzyme telomerase — lose DNA from the tips of their chromosomes (telomeres) with each cell division. In general, the telomeres in the cells of old animals are much shorter than those in young animals.
A recent study of short-lived versus long-lived birds showed that telomere shortening was faster in the short-lived species. And one species, a petrel which lives four times as long as other birds of its size, actually has telomeres that grew longer with age.
Most somatic cells of the body cease to express telomerase. (Germ cells, some stem cells, and cancer cells continue to express the enzyme.)
If telomeres get too short, chromosome abnormalities — a hallmark of cancer — occur. These can be avoided if the cell senses this dangerous condition and ceases to divide. The p53 protein may mediate the signal calling for stopping the cell cycle. The result: replicative senescence.
Evidence: Cells genetically manipulated to express telomerase long after they should have stopped, avoid replicative senescence.
So replicative senescence may be the price we pay for removing cells from the cell cycle before they can accumulate the mutations that would turn them into cancer cells.
How would replicative senescence of cells lead to the deterioration in structure and function of the aging tissues (e.g., skin) in which they reside? In tissues, e.g., skin and other epithelia, where mitosis must continue throughout life to replace the cells that are lost, the accumulation of senescent cells —incapable of further mitosis — could leading to the characteristic changes of aging in that tissue.
One mechanism could be simply the loss of cells able to repair the tissue by mitosis. However, senescent cells are still active although the genes they express change. Perhaps the proteins they secrete (e.g., collagen-digesting enzymes) cause the aging changes in the tissue where they reside.
4. The Accumulation of Genetic Errors?
Effect of radiation on aging.
These mice are all 14 months old. As young adults, nine mice were given sublethal doses of radiation and nine others were left as untreated controls. The control mice (left) are still sleek and vigorous at 14 months, while six of the irradiated mice have died and the remaining three show signs of extreme aging (right). [Research photographs of Dr. Howard J. Curtis.]
The pros
Mice given ionizing radiation that damages DNA show early aging. Transgenic mice with a defect in the "proofreading" function of the DNA polymerase responsible for copying mitochondrial DNA
accumulate many mutations in their mitochondrial genes; show marked signs of premature aging.
Cells taken from old mice (and old humans) show slightly elevated levels of somatic mutations and chromosome abnormalities like translocations and aneuploidy. Many of these changes also cause cancer so it is no accident that the incidence of cancer rises with advancing age (graph). Cells taken from old people (and people with premature aging syndromes) show marked reductions in the transcription of many genes.
Clues from the Transcriptome of Aging Brains
A group of Harvard researchers reported (in the 26 June 2004 issue of Nature) the results of their study of gene expression in the human brain.
They extracted the RNA from autopsied brain tissue of 30 people who had died at ages ranging from 26 to 106. They analyzed the RNA with DNA chips looking for the level of activity of some 11,000 different genes (the transcriptome). A clear pattern emerged.
The level of activity of some 400 genes changed over time.
Gene expression declined in old age for many genes. Some examples:
genes encoding proteins involved in synaptic activity in the brain (e.g., learning, memory)
NMDA, AMPA, GABAA receptors calcium-calmodulin-dependent kinase II (CaMKII)
genes involved in mitochondrial functions, such as
production of ATP (needed for DNA repair) production of damaging reactive oxygen species (ROS)
Detailed examination of some of these down-regulated genes showed that they had suffered DNA damage — more often in their promoters than in their coding regions. Gene expression increased in old age for other genes. Some examples:
genes involved in inflammation and other immune defenses; genes encoding proteins involved in defense against reactive oxygen species (ROS); genes encoding proteins involved in DNA repair.
The transition from the youthful transcriptome to the transcriptome of the aged brain occurred at varying times from as young as 42 to as old at 73 (my age).
Clues from Premature Aging Syndromes
Humans suffer from a number of rare genetic diseases that, among other things, produce signs of premature aging, e.g., gray hair, wrinkled skin, and shortened life span. In several cases, the mutated genes are ones that have roles to play in maintaining the integrity of the genome, that is, in DNA repair.
Werner's syndrome. The hair of patients turns gray in their 20s and most die in their late 40s with such signs of age as osteoporosis, cataracts, and atherosclerosis. Even when young, their cells undergo replicative senescence after only ~20 doublings instead of the normal 70 or more. Caused by mutations in WRN, which encodes a helicase needed for DNA repair and maintenance of telomeres. Cockayne syndrome (CS). Caused by mutations in genes needed for DNA repair, especially transcription-coupled DNA repair. While these people show only some of the signs of aging, they do have a sharply-reduced life span. Ataxia telangiectasia (AT). These patients show signs of premature aging. They lack a functioning gene (ATM) product needed to detect DNA damage and initiate a repair response. Hutchinson-Gilford progeria syndrome. Children with this rare disorder show many signs of severe aging by their second birthday and die in their early teens. Caused by mutations in the gene (LMNA) for lamin the intermediate filament protein that stabilizes the inner membrane of the nuclear envelope.
The first three cases suggest that aging may be the consequence not so much of mutations in general, but of mutations in those genes whose products are essential for the error-free
replication repair, and transcription
of all genes.
The cons
Hutchinson-Gilford progeria syndrome does not seem to involve DNA repair. However, nuclear lamins, do anchor chromosomes and perhaps defective lamins can also lead to genome instability.
Why is a mouse as old at 2 years as a human at 70?
Correlation between life span and the relative effectiveness of DNA repair in cells of certain mammals. In each case, cells growing in tissue culture were irradiated with ultraviolet light and then the efficiency with which they repaired their DNA was determined. (From the work of R. W. Hart and R. B. Setlow, 1974.)
Species Average life span, yr Relative effectiveness of DNA repair
Human 70 50
Elephant 60 47
Cow 30 43
Hamster 4 26
Rat 3 13
Mouse 2 9
Shrew 1 8
If aging represents the inevitable consequence of a failure of DNA repair, why does it occur so much sooner in some mammals (e.g., mice) than in others (e.g., elephants and humans)?
The answer probably lies in the risk of death from external factors (e.g., predation, starvation, cold) in that species.
As noted above, few small mammals ever age because they die early of external causes. These animals are r-strategists, putting their energy into quickly
reaching sexual maturity; producing large numbers of offspring that can soon live independently.
There is no selective advantage for them to invest in the machinery of efficient DNA repair because they are going to die before mutations become a problem. Humans, in contrast, are K-strategists. They
take a long time to reach sexual maturity; produce small numbers of young that must be cared for over a long period.
Small wonder, then, that evolution in humans (and other long-lived mammals) has selected for genes promoting efficient DNA repair.
The table shows that the efficiency of DNA repair is directly correlated with life span in a variety of mammals.
Interrelationships
Examining the various factors that have been implicated in the aging process suggests that most —perhaps all — are interrelated.
High metabolic rate with the production of reactive oxygen species with their damaging effect on DNA and other cell constituents coupled with the onset of replicative senescence so that damaged cells can no longer be replaced
may all play important roles. So the factors described above are by no means mutually exclusive.
Aging in Plants
Annuals and Biennials
Annuals, such as many grasses and "weeds"
grow vigorously for a period; then form flowers followed by fruits. Fruiting is followed by a slowing of growth accompanied by physiological and morphological changes such as
an increase in the rate of respiration (catabolism) loss of chlorophyll
These changes constitute aging and end in the death of the plant.
Biennials follow the same pattern, but take two years to do it.
This pattern in clearly programmed in the genes. Even with plentiful moisture, soil minerals, sunlight, and warm temperatures, the plants age and die.
Perennials
The situation is quite different in perennials. Throughout their lives, woody perennials (trees) produce new vascular tissue, leaves, and flowers each year. They do not show marked signs of aging, although their rate of growth may decline over the years. Finally, disease or inability to support their ever-increasing size against wind or snow load lead to their death.
This picture (courtesy of Walter Gierasch) is of bristlecone pines (Pinus aristata) growing in the White Mountains of eastern California. Tree-ring analysis shows that many of these trees are over 4000 years old. But note that no living cells in the tree are more than a few years old.
