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Considering that dying "from old age" actually means that one dies from an illness related with aging, is it inevitable to eventually acquire diseases in old age?
There is a thought that aging itself should be considered a disease. In which case, death by disease is inevitable with our current level of medical technology.
During the last 25 years, by targeting the underlying processes of aging biomedical scientists have been able to improve the health and lifespan of model organisms, from worms and flies, to rodents and fish. We can now consistently improve the lifespan of C. elegans by more than ten-fold (Ayyadevara et al., 2008), more than double the lifespan of flies and mice (Bartke et al., 2001; Sun et al., 2002), and improve the lifespan of rats and killifish by 30 and 59%, respectively (Valenzano et al., 2006; Zha et al., 2008) (see Figure Figure11 and Supplementary Table 1). Currently, our treatment options for the underlying processes of aging in humans are limited. However, with current progress in the development of geroprotective drugs, regenerative medicine, and precision medicine interventions, we will soon have the potential to slow down aging (Bulterijs, 2011, 2012).
Aging is not synonymous with disease, and hence it is generalized as such, although vulnerability to diseases does increases over time.
Why is it not a disease? Well biological aging can be defined as:
A process of progressive, intrinsic, and generalized physical deterioration that occurs over time (begins at the age of maturity).
While a disease is:
An abnormal condition of an organism which interrupts the normal bodily functions that often leads to a feeling of pain and weakness, and usually associated with symptoms and signs.
Now let's look as to why we cannot live forever and as to why as we get old our disease susceptibility will be (in general) increased, meaning that yes the majority of the population will be dying from a form of a disease. If not a disease it will be a failure of the body system to maintain life.
I will be looking at this in the form of Natural Selection.
The force of Natural Selection declines with age. For example, a gene that is beneficial during young age, but bad during old age (such as making you susceptible to several diseases) will spread in the population because it will manifest after you've reproduced.
Example#1: A gene that helps achieve good blood coagulation and prevents hemorrhage in young people will spread in the population. However, in old aged people, it will cause an increased risk of stroke. Such associations have been previously found for many genes associated with blood characteristics.
Example#2: Overproduction of sex hormones in young age is beneficial for reproduction but will cause prostate and ovarian cancer later in life.
This is called Antagonistic Pleiotropy
In addition, Natural selection is not concerned with late acting mutations.
So as we age will we be afflicted by a disease? Most likely yes, it depends on the trends in disease prevalence which have changed throughout the years due to preventative medicine. If we do not acquire any death-inflicting (be it slow or fast acting) disease, our body will give up before we do get one.
If you'd like to look at disease prevalence, chronic illnesses throughout the years, or the specific trends in a year, just go over to the CDC's webpage.
"Old age" diseases are fundamentally malfunctions because stuff breaks. Some blame this on shortening telomeres, although an equally big part of the problem is that there are way too many important pieces that are unable to regenerate themselves.
Think of it as a machine where you can't normally get replacement parts. Stuff wears out, goes off warranty, and breaks.
Experimental regenerative medicine is working on fixing that with 3 fundamental approaches:
Adult pluripotent stem cells/regrowth. Researchers are looking for growth/regrowth/cell proliferation and differentiation mechanisms that already exist so they can be leveraged to regrow stuff that normally doesn't regrow. The advantage is that all the parts are grown from your own DNA or cells which means minimal problems with rejection or incompatibility. As an added bonus it could be considered "all natural". The main risk is cancer due to misconfigured cell growth/proliferation.
Lab-grown or 3D-printed replacement. Higher risk of rejection and other problems but simple and cheap compared to the others. Some research includes growing human-cell transplants in animals which raises various ethical and safety concerns.
Cybernetics or machine implants. Probably the most expensive and works out the best… when it works properly. "Robot" parts keep getting better and better, and have the bonus that they are more readily reprogrammable than DNA and biochemistry. A prominent research area includes brain/nerve interfaces with machine parts - expect pieces that either adapt to neural outputs or connect to nerves so you can "learn" how to use them. The main drawbacks of this approach other than the cost include vulnerability to EMPs (a massive solar flare or EMP attack will fry all unprotected cybernetics/implants/robot parts), being dependent on both electricity and regular food, risk of getting hacked, and general lack of self-repairability short of replacing parts that break (again). Alternately you could argue that the risk of getting hacked through cybernetic implants and robot parts is a fair tradeoff considering they're immune to organic viruses and infections (except if someone invents bacteria that eat through solid metal or plastic pieces)
In humans, are diseases inevitable during old age? - Biology
The aging process often results in a loss of memory, deteriorated intellectual function, decreased mobility, and higher rates of disease.
Review the physical and neurological changes characteristic of late adulthood
- During late adulthood the skin continues to lose elasticity, reaction time slows further, muscle strength and mobility diminishes, hearing and vision decline, and the immune system weakens.
- The aging process generally results in changes and lower functioning in the brain, leading to problems like decreased intellectual function and neurodegenerative diseases such as Alzheimer’s.
- Many of the changes in the bodies and minds of older adults are due in part to a reduction in the size of the brain as well as loss of brain plasticity.
- Memory degenerates in old age, so older adults have a harder time remembering and attending to information. In general, an older person’s procedural memory tends to remain stable, while working memory declines.
- cerebellum: Part of the hindbrain in vertebrates in humans it lies between the brainstem and the cerebrum and plays an important role in sensory perception, motor output, balance, and posture.
- Alzheimer’s disease: A disorder involving loss of mental functions resulting from brain-tissue changes a form of senile dementia.
- corpus callosum: In mammals, a broad band of nerve fibers that connects the left and right hemispheres of the brain.
- neurodegenerative: Of, pertaining to, or resulting in the progressive loss of nerve cells and of neurologic function.
Late adulthood is the stage of life from the 60s onward it constitutes the last stage of physical change. Average life expectancy in the United States is around 80 years however, this varies greatly based on factors such as socioeconomic status, region, and access to medical care. In general, women tend to live longer than men by an average of five years. During late adulthood the skin continues to lose elasticity, reaction time slows further, and muscle strength diminishes. Hearing and vision—so sharp in our twenties—decline significantly cataracts, or cloudy areas of the eyes that result in vision loss, are frequent. The other senses, such as taste, touch, and smell, are also less sensitive than they were in earlier years. The immune system is weakened, and many older people are more susceptible to illness, cancer, diabetes, and other ailments. Cardiovascular and respiratory problems become more common in old age. Seniors also experience a decrease in physical mobility and a loss of balance, which can result in falls and injuries.
Changes in the Brain
The aging process generally results in changes and lower functioning in the brain, leading to problems like memory loss and decreased intellectual function. Age is a major risk factor for most common neurodegenerative diseases, including mild cognitive impairment, Alzheimer’s disease, cerebrovascular disease, Parkinson’s disease, and Lou Gehrig’s disease.
While a great deal of research has focused on diseases of aging, there are only a few informative studies on the molecular biology of the aging brain. Many molecular changes are due in part to a reduction in the size of the brain, as well as loss of brain plasticity. Brain plasticity is the brain’s ability to change structure and function. The brain’s main function is to decide what information is worth keeping and what is not if there is an action or a thought that a person is not using, the brain will eliminate space for it.
Photos depicting the progression of Alzheimer’s disease: Alzheimer’s disease (AD) is a neurodegenerative disease and is the most common form of dementia in older adults.
Brain size and composition change along with brain function. Computed tomography (CT) studies have found that the cerebral ventricles expand as a function of age in a process known as ventriculomegaly. More recent MRI studies have reported age-related regional decreases in cerebral volume. The brain begins to lose neurons in later adult years the loss of neurons within the cerebral cortex occurs at different rates, with some areas losing neurons more quickly than others. The frontal lobe (which is responsible for the integration of information, judgement, and reflective thought) and corpus callosum tend to lose neurons faster than other areas, such as the temporal and occipital lobes. The cerebellum, which is responsible for balance and coordination, eventually loses about 25 percent of its neurons as well.
Changes in Memory
Memory also degenerates with age, and older adults tend to have a harder time remembering and attending to information. In general, an older person’s procedural memory stays the same, while working memory declines. Procedural memory is memory for the performance of particular types of action it guides the processes we perform and most frequently resides below the level of conscious awareness. In contrast, working memory is the system that actively holds multiple pieces of transitory information in the mind where they can be manipulated. The reduced capacity of the working memory becomes evident when tasks are especially complex. Semantic memory is the memory of understanding things, of the meaning of things and events, and other concept-based knowledge. This type of memory underlies the conscious recollection of factual information and general knowledge about the world, and remains relatively stable throughout life.
Physiology sets only very broad limits on human sexuality most of the enormous variation found among humans must be attributed to the psychological factors of learning and conditioning.
The human infant is born simply with the ability to respond sexually to tactile stimulation. It is only later and gradually that the individual learns or is conditioned to respond to other stimuli, to develop a sexual attraction to males or females or both, to interpret some stimuli as sexual and others as nonsexual, and to control in some measure his or her sexual response. In other words, the general and diffuse sexuality of the infant becomes increasingly elaborated, differentiated, and specific.
The early years of life are, therefore, of paramount importance in the development of what ultimately becomes adult sexual orientation. There appears to be a reasonably fixed sequence of development. Before age five, children develop a sense of gender identity, think of themselves as boys or girls, and begin to relate to others differently according to their gender. Through experience children learn what behaviour is rewarded and what is punished and what sorts of behaviour are expected of them. Parents, peers, and society in general teach and condition children about sex not so much by direct informational statements and admonitions as by indirect and often unconscious communication. Children soon learn, for example, that they can touch any part of their body or someone else’s body except the anal–genital region. Children rubbing their genitals find that this quickly attracts adult attention and admonishment or that adults will divert them from this activity. It becomes clear that there is something peculiar and taboo about this area of the body. This “genital taboo” is reinforced by the great concern over children’s excretory behaviour: bladder and bowel control is praised loss of control is met by disappointment, chiding, and expressions of disgust. Obviously, the anal–genital area is not only a taboo area but a very important one as well. It is almost inevitable that the genitalia become associated with anxiety and shame. It is noteworthy that this attitude finds expression in the language of Western civilizations, as in “privates” (something to be kept hidden) and the German word for the genitals, Scham (“shame”).
While all children in Western civilizations experience this antisexual teaching and conditioning, a few have, in addition, atypical sexual experiences, such as witnessing or hearing sexual intercourse or having sexual contact with an older person. The effects of such atypical experiences depend upon how children interpret them and upon the reaction of adults if the experience comes to their attention. Seeing parental coitus is harmless if children interpret it as playful wrestling but harmful if they consider it as hostile, assaultive behaviour. Similarly, an experience with an adult may seem merely a curious and pointless game, or it may be a hideous trauma leaving lifelong psychic scars. In many cases the reaction of parents and society determines the child’s interpretation of the event. What would have been a trivial and soon-forgotten act becomes traumatic if the mother cries, the father rages, and the police interrogate the child.
Some atypical developments occur through association during the formative years. A child may associate clothing, especially underclothing, stockings, and shoes with gender and sex and thereby establish the basis for later fetishism or transvestism. Others, having been spanked or otherwise punished for self-masturbation or childhood sex play, form an association between punishment, pain, and sex that could escalate later into sadism or masochism. It is not known why some children form such associations whereas others with apparently similar experience do not.
About the age that children enter puberty, parents and society, who more often than not refuse to recognize that children have sexual responses and capabilities, finally face the inescapable reality and consequently begin inculcating children with their attitudes and standards regarding sex. This campaign by adults is almost wholly negative: the child is told what not to do. While dating may be encouraged, no form of sexual activity is advocated or held up as model behaviour. The message usually is: “Be popular [i.e., sexually attractive] but abstain from sexual activity.” This antisexualism is particularly intense regarding young females and is reinforced by reference to pregnancy, sexually transmitted diseases, and, most importantly, social disgrace. To this list religious families add the concept of the sinfulness of premarital sexual expression. With young males the double standard of morality still prevails. The youth receives a double message: “Don’t do it, but we expect that you will.” No such loophole in the prohibitions is offered young girls. Meanwhile, the young male’s peer group is exerting a prosexual influence, and his social status is enhanced by his sexual exploits or by exaggerated reports thereof.
As a result of this double standard of sexual morality, the relationship between young males and females often becomes a ritualized contest, the male attempting to escalate the sexual activity and the female resisting his efforts. Instead of mutuality and respect, one often has a struggle in which the female is viewed as a reluctant sexual object to be exploited, and the male is viewed as a seducer and aggressor who must succeed in order to maintain his self-image and his status with his peers. This sort of pathological relationship causes a lasting attitude on the part of females: men are not to be trusted they are interested only in sex a girl dare not smile or be friendly lest males interpret it as a sign of sexual availability, and so forth. Such an aura of suspicion, hostility, and anxiety is scarcely conducive to the development of warm, trusting relationships between males and females. Fortunately, love or infatuation usually overcomes this negativism with regard to particular males, but the average female still maintains a defensive and skeptical attitude toward men.
Western society is replete with attitudes that impede the development of a healthy attitude toward sex. The free abandon so necessary to a full sexual relationship is, in the eyes of many, an unseemly loss of self-control, and self-control is something one is urged to maintain from infancy onward. Panting, sweating, and involuntary vocalization are incompatible with the image of dignity. Worse yet is any substance once it has left the body: it immediately becomes unclean. The male and female genital fluids are generally regarded with disgust—they are not only excretions but sexual excretions. Here again, societal concern over excretion is involved, for sexual organs are also urinary passages and are in close proximity to the “dirtiest” of all places—the anus. Lastly, many individuals in society regard menstrual fluid with disgust and abstain from sexual intercourse during the four to six days of flow. This attitude is formalized in Judaism, in which menstruating females are specifically labelled as ritually unclean.
In view of all these factors working against a healthy, rational attitude toward sex and in view of the inevitable disappointments, exploitations, and rejections that are involved in human relationships, one might wonder how anyone could reach adulthood without being seriously maladjusted. The sexual impulse, however, is sufficiently strong and persistent and repeated sexual activity gradually erodes the inhibitions and any sense of guilt or shame. Further, all humans have a deep need to be esteemed, wanted, and loved. Sexual activity with another is seen as proof that one is attractive, desired, valued, and possibly loved—a proof very necessary to self-esteem and happiness. Hence, even among the very inhibited or those with weak sex drive, there is this powerful motivation to engage in sociosexual activity.
Most persons ultimately achieve at least a tolerable sexual adjustment. Some unfortunates, nevertheless, remain permanently handicapped, and very few completely escape the effects of society’s antisexual conditioning. While certain inhibitions and restraints are socially and psychologically useful—such as deferring gratification until circumstances are appropriate and modifying activity out of regard for the feelings of others—most people labour under an additional burden of useless and deleterious attitudes and restrictions.
Aging Is About Evolution
Technically, there is really no reason that the human body should "wear out," as long as it can repair and renew itself. Therefore, something other than time must be at play to cause the inevitable effects of aging.
The programmed theory of aging asserts that aging and death are necessary parts of evolution, not of biology. If a species did not have the genetic capacity for aging and death, then it would not be forced to replicate to survive.
Individuals in the species would just keep on living until a climate or other change wiped them all out. The key point here is that if biological individuals live forever, evolution would not exist.
The jellyfish Turritopsis dohrnii uses reprogramming to become biologically immortal.
Although reprogramming works to reverse age of a single cell, there is also an example of a similar type of reprogramming working to reverse the age of an entire organism. As a second indication that reprogramming is key to age reversal, scientists have found that the technique is used by the jellyfish Turritopsis dohrnii to stay immortal. This animal has been reported to have a seemingly infinite lifespan, and is one of the only organisms on the planet with this property.
Interestingly enough, as opposed to being resistant to the processes of time, this jellyfish lives forever by constantly transforming into an immature state. If the jellyfish is sick or old, it performs a transformation act and reverts all of its cells from an adult state into an earlier developmental form called the “polyp” state, much like what happens during reprogramming of single cells. Once in the polyp state, the jellyfish can then re-mature as a healthy adult. Because it can do this continuously, the jellyfish theoretically has an immortal biological age.
While this also would not directly work as a therapeutic strategy in humans, it further indicates that resetting cell state through reprogramming can be used to reverse age within a living organism, and by exploring reprogramming, we might learn how to truly replenish health and fitness.
Medical myths: All about aging
In the latest installment of our Medical Myths series, we tackle myths associated with aging. Because aging is inevitable and, for some people, frightening, it is no surprise that myths abound.
Share on Pinterest Addressing the “inevitabilities” of aging.
Around 300,000 generations ago, the human species split from an ancient ancestor that we share with chimpanzees. Since then, human life expectancy at birth has doubled.
Over the last 200 years, life expectancy at birth has doubled again. As animals go, humans perform well in longevity.
According to the World Health Organization (WHO), &ldquoBetween 2000 and 2050, the proportion of the world&rsquos population over 60 years will double from about 11% to 22% .&rdquo
With these facts in mind, dispelling the many myths associated with aging seems more pressing than at any point in our evolutionary history. In this article, we will tackle myths associated with exercise, cognitive ability, sex, and more.
This is not entirely untrue. As we age, our body does experience wear and tear from decades of use. However, physical deterioration does not have to be complete, and people can often slow it down.
As the WHO explain, &ldquoIncreased physical activity and improving diet can effectively tackle many of the problems frequently associated with old age.&rdquo These problems include reduced strength, increased body fat, high blood pressure, and reduced bone density.
Some research suggests that merely expecting physical deterioration increases the likelihood that someone will physically deteriorate.
In one study , scientists surveyed 148 older adults about their aging, lifestyles, and general health expectations.
They concluded that expectations regarding aging &ldquoplay an important role in the adoption of physically active lifestyles in older adults and may influence health outcomes, such as physical function.&rdquo
So, although some deterioration is likely, managing expectations will help individuals make better life choices to maintain physical health and fitness later in life.
An older study investigated how perceptions of aging influenced an individual&rsquos likelihood of seeking medical attention. The authors of the study, which included data from 429 older adults , concluded:
&ldquo[H]aving low expectations regarding aging was independently associated with not believing it important to seek health care.&rdquo
Another study looked at individual attitudes to aging during late middle-age and how they might influence their overall lifespan. The authors concluded that &ldquoolder individuals with more positive self-perceptions of aging, measured up to 23 years earlier, lived 7.5 years longer than those with less positive self-perceptions of aging.&rdquo
In short, keeping active, eating right, and maintaining a positive outlook can often slow the physical deterioration associated with older age.
From the previous section, it is clear that this is a myth. According to an older article in Neuropsychobiology, keeping active can boost muscle strength, reduce fat, and improve mental health.
Some people think that, once they reach a certain age, there is no point in exercising, as they believe that it will provide no benefit. This is another myth. In one study , researchers put 142 adults aged 60&ndash80 through a 42-week weight-lifting regime.
The scientists found that the course increased &ldquodynamic muscle strength, muscle size, and functional capacity.&rdquo
There is also good evidence that regular exercise can reduce the risk of developing Alzheimer&rsquos disease and other forms of dementia. A study, which involved 1,740 older adults, found that regular exercise was &ldquoassociated with a delay in onset of dementia and Alzheimer&rsquos disease.&rdquo
However, people should consult their doctor before embarking on a new exercise regime if they have a medical condition. For example, the National Health Service (NHS) in the United Kingdom indicate that people with certain conditions associated with age, such as osteoporosis, should avoid high impact exercise.
However, the vast majority of older adults can indulge in some form of physical activity.
Some people believe that older adults need more sleep than younger adults, perhaps because of the stereotype that older people enjoy a nap. Others say that older adults need less sleep, which might stem from the stereotype that older adults rise early in the morning.
These myths are relatively difficult to unpick because there are many factors involved. It is undoubtedly true that older adults have more difficulty getting to sleep and that their sleep tends to be more fragmented .
This might help explain why some older adults need to nap in the day. As the human body changes with age, it can disrupt the circadian (daily) rhythms.
This, in turn, can impact sleep. The relationship is multifaceted, too: if a person&rsquos circadian rhythms become disrupted, it can influence other aspects of their physiology, such as hormone levels, which might also impact their sleep.
Aside from circadian disruptions, certain diseases that occur more commonly in older adults, such as osteoarthritis and osteoporosis, can cause discomfort, which might adversely influence an individual&rsquos ability to get to sleep or stay asleep.
Similarly, some conditions cause shortness of breath, including chronic obstructive pulmonary disease (COPD) and congestive heart failure this can also make sleeping more challenging.
According to an older article , certain medications, including beta-blockers, bronchodilators, corticosteroids, decongestants, and diuretics, can also interfere with sleep. Older adults are more likely to be taking these types of medication, sometimes together.
The Centers for Disease Control and Prevention(CDC) state that people aged 61&ndash64 need 7&ndash9 hours, and people aged 65 or older need 7&ndash8 hours of sleep each night. It just might be more difficult for them to get that all-important shut-eye.
As a silver lining, some research suggests that older adults can handle sleep deprivation better than young adults. A study in the Journal of Sleep Research found that older adults scored better following a sleep deprivation intervention than younger adults in a range of measures, including negative affect, depression, confusion, tension, anger, fatigue, and irritability.
Why Aging Isn’t Inevitable
H umans age gradually, but some animals do all their aging in a rush at the end of life, while others don’t age at all, and a few can even age backward. The variety of aging patterns in nature should be a caution sign to anyone inclined to generalize—particularly the generalization that aging is inevitable.
Bacteria reproduce symmetrically, just dividing in two. What could “aging” mean for bacteria since, after reproduction, there is no distinction between parent and child? Single-cell protists like the amoeba also reproduce symmetrically, but curiously, they invented a way to age nevertheless. And even among macroscopic life forms, life spans of organisms are immensely variable in a way that is finely tuned to local ecologies and reproduction rates. This can hardly be the result of a universal, inexorable process in fact, such fine-tuning to circumstance is the signature of an adaptation.
Sudden Death: Mayflies, like the ones in this pile, tend to die rapidly and suddenly at the end of their reproductive cycle. Fecundap Stock
Life spans range from Methuselans great and small to genetic kamikazes that die of a spring afternoon. Submerged dragonflies live four months, adult mayflies half an hour. We live some 70-odd years but the meristem of the ginkgo may be millions of years old. This range becomes all the more impressive when we realize that the genetic basis for aging is widely shared across different species, from yeast cells on up to whales. Somehow, the same genetic machinery, inherited from our common ancestors at the dawn of life on Earth, has been molded to generate life spans ranging from hours (yeast cells) to thousands of years (sequoia trees and quaking aspen).
And it is not only the length of life but the pattern of deterioration within that time that varies widely. Aging can occur at a steady pace through the course of an entire lifetime (most lizards and birds), or there can be no aging at all for decades at a time, followed by sudden death (cicadas and century plants).
Our own “inner assassin” works with stealth, like an evil empress gradually poisoning her husband but other species have inner killers that do their deed far more quickly, and still others appear to have no genetic death programs at all. Such variety is a sure signal for a feature molded by active natural selection, not an immutable law of entropy.
The Real Secret of Youth Is Complexity
Simplicity, simplicity, simplicity!” Henry David Thoreau exhorted in his 1854 memoir Walden, in which he extolled the virtues of a “Spartan-like” life. Saint Thomas Aquinas preached that simplicity brings one closer to God. Isaac Newton believed it leads to truth. READ MORE
A s the biomarkers of aging vary widely from one species to the next—indeed, from one individual to the next—it’s difficult to come up with a single universal definition. A man may be prematurely gray, and a naked mole rat baby may be covered with wrinkles. For the actuary, however, the question has a clear answer, even if it’s one only a statistician could love: Aging is an increase in the mortality rate. In other words, as an animal gets older, it suffers an ever-higher risk of death.
For example, a 20-year-old man has 99.9 percent chance of living to see his 21st birthday. This is to say that his chance of dying is 1 in 1,000 per year. If this were to continue, then a 40-year-old would also have a 1 in 1,000 chance of dying before his 41st birthday. We’d call that “no aging.” In reality, a 40-year-old has a 2 in 1,000 chance of dying before his 41st birthday. This doubling of his mortality risk over 20 years is evidence of gradual aging.
It gets worse. The risk for a 60-year-old is 10 in 1,000 and for an 80-year-old, 60 in 1,000.
Life and Death: This table breaks down the odds that a human will die at various ages. As humans grow older, the chance of death goes up dramatically. Data from the Social Security actuarial tables for 2010.
Not only does the risk of dying increase, it increases faster and faster. An increase in the deterioration or the chances of dying with each passing year, such as occurs in us after reaching adulthood, is called “accelerating senescence.” But other species have different patterns. The probability of death may increase and then level out: “decelerating senescence,” or even a “mortality plateau.” If we commit to this definition for aging, we are bound to say that if the probability of death doesn’t increase, then the species doesn’t age at all. It is consistent, if stranger, to say that if the probability of death goes down from one year to the next that a species is aging backward, which is called “negative senescence.”
There’s a second objective measure of aging, and that is decline in fertility. Just as mortality is defined as the probability of death, fertility is defined as the probability of reproduction. Men lose fertility gradually over their adult life. Women lose their fertility more rapidly, and fertility drops to zero at menopause. But different species have different patterns, different schedules. In some species, fertility increases over much of the life span, another form of “negative senescence.”
For example, Blanding’s turtle, a species of box turtle common in the American Midwest, matures slowly over decades, and it doesn’t keep growing, but it does continue to increase in fertility. Apparently, its risk of dying also declines with age. From an evolutionary perspective, the loss of fertility is primary. From the perspective of natural selection, once you’re no longer able to reproduce, you might as well be dead.
Nature can do whatever she wishes with aging (or non-aging). Any time scale is possible, and any shape is possible.
We find it natural to classify different species as living a long or a short time, to lump together the insects that live for a day and distinguish them from the trees and whales that live hundreds of years. But much of that difference can be attributed to size. Everything from growth to reproduction to aging must occur more slowly in a behemoth with a slow metabolism and tons of tissue to nourish. So we are inclined to be more impressed with a honeybee that lives 20 years than we are with a moose that lives 20 years.
But suppose we were to remove length of life completely from consideration and compare different species based on the shape rather than the duration of their life histories. However long or short the life span, we display it in the same size box for comparison. Rather than asking how long they live, ask instead whether their populations tend to die out gradually, or if many die in infancy and fewer later on, or if all the deaths bunch up at the end of the life cycle. A chart published in a paper in Nature in 2014 does just this, and what emerges from this picture is the breadth of nature’s ingenuity. Every conceivable combination is represented, with rapid aging and no aging and backward aging, paired with life spans of weeks or years or centuries. The strange bedfellows that appear as neighbors on the chart are utterly unexpected. For example, at the top of the chart, with low mortality that rises suddenly at the end of life, humans are joined by lab worms and tropical fish (guppies)! In fact, in terms of aging profiles, we humans look more like the lab worm than the chimpanzee.
The above graphs show the varieties of ways that animals and plants age in the wild. The light downward line in each frame is the survival curve, and the bold curve underneath is fertility. The downward slope of the survival line just means that fewer and fewer individuals are left alive as time goes on. The way this graph has been constructed, a straight line going diagonally downward is neutral, or no aging at all. Lines that are humped over the diagonal represent normal aging, while lines that curve under the diagonal represent reverse aging, or “negative senescence.” For example, the line for humans stays flat for a long while and then descends sharply that means that many people are living out a full life span, and then their deaths are all clustered in their 80s and 90s (the stats were recorded for modern-day Japan).
But for animals and plants in the bottom two rows, the death rates are steadier. For turtles and oak trees, in fact, the curves flatten out. That means that there are less of them dying old than dying young, which is aging in reverse.
The bold line, representing fertility, is straightforward. Fertility may rise as an animal or plant grows bigger, or it may fall with reproductive aging—for example, in menopause. Notice that animals in the top row lose all their fertility well before they are dead. This poses an evolutionary conundrum in its own right. 1
In this diagram, if the survival curve is a straight diagonal, that corresponds to no aging—for example, the hydra and the hermit crab. (The hydra is like a freshwater jellyfish, a quarter inch long and found in ponds.) All the animals in the top row show “true aging”—they are more likely to die as they get older. The next two rows show plants and animals that don’t age or that age in reverse. For the latter case, the older they are, the less the risk of death. Most trees are like this, and tortoises follow the same pattern, as do clams and sharks (not pictured).
The lower, bold curve in each frame is fertility. Animals in the top row stop reproducing well before they are likely to die. This poses an evolutionary conundrum for neo-Darwinist orthodoxy—if the sole target of natural selection is to maximize reproduction, then why has evolution allowed reproduction to fall to zero while so many remain alive? The rising fertility curves indicate increased reproduction with age, which is another kind of negative senescence. When you think about a tree that grows larger with each passing year, it’s not so surprising that it’s making more seeds the older it gets. The Spanish mountain plant in the third row is Borderea pyrenaica, a plant that grows out on the rocky cliffs of the Pyrenees mountains. If undisturbed, it can live to 300 years or more with no sign of aging but notice that its fertility doesn’t really get going until it is more than 20 years old.
The message of this diagram is nature can do whatever she wishes with aging (or non-aging). Any time scale is possible, and any shape is possible, and each species is exquisitely adapted to its ecological circumstance. There are no constraints.
Aging to death can be rapid and sudden at the end of a reproductive cycle. Sudden post-reproductive death is common in nature, affecting organisms as varied as mayflies, octopuses, and salmon, not to mention thousands of annual flowering plants. Biologists refer to this life story as “semelparity” (from Latin “single birth”).
The cause of death in semelparous organisms varies widely. Octopuses just stop eating. Praying mantis males make an ultimate reproductive sacrifice, giving themselves up as snacks to their female partners. Salmon destroy their own bodies with a blaze of steroids.
By the time the adult salmon reach their spawning ground, their metabolisms are in terminal collapse. Their adrenal glands are pumping out steroids (glucocorticoids) that cause accelerated—almost instant—aging. They’ve stopped eating. Moreover, the steroids have caused their immune systems to collapse, so their bodies are covered with fungal infections. Kidneys atrophy, while the adjacent cells (called interregnal cells, associated with the steroids) become greatly enlarged. The circulatory systems of the rapidly deteriorating fish are also affected. Their arteries develop lesions that, interestingly, appear akin to those responsible for heart disease in aging humans. The swim upstream is arduous, but it is not the mechanical beating that fatally damages their bodies. It is rather a cascade of nasty biochemical changes, genetically timed to follow on the heels of spawning.
Some organisms are genetically programmed not to eat after reproduction and starve as a result it’s quicker and surer than traditional aging. Mayflies entering adulthood have no mouth or digestive system whatever. Elephants chomp and grind so many stalks and leaves during a lifetime that they wear out six full sets of teeth. But when the sixth set is gone, they won’t grow another, and the pachyderms starve to death.
Queen bees show no symptoms of senescence. They are ageless wonders.
In 2014, photographer Rachel Sussman published a coffee-table volume of her ancient subjects entitled, The Oldest Living Things in the World. All of them are plants. One reason for this, at least in comparison to ambulatory animals, is that plants don’t have to worry about leg muscles strong enough to walk. Confined to one location, they can grow larger and sturdier, older and far more fertile than any animal, and reap the benefits of seniority.
Plants have another longevity secret. Early in the life of a developing animal, the sex cells, or germ line, segregate from the rest of the body, or soma. Only the germ line must be preserved immaculate to become the next generation the body can afford to be sloppier with cells of the soma and take shortcuts as they reproduce themselves. But plants have a different system. The germ line and soma never really segregate. Plants, like animals, have stem cells, and in plants those stem cells give rise not only to new plant growth but also to the seeds and pollen that is destined to become the next generation. In a tree, the stem cells are located in a thin layer under the bark, called the meristem. The meristem extends into every branch and twig of the tree and gives rise to new leaves and also to buds and seeds. In some ginkgoes, nonflowering trees that date back to the Permian 270 million years ago, this meristem layer may be millions of years old.
Still, it seems that most trees have a characteristic age, after which death finally becomes more likely with each passing year. Shoots (“epicormic sprouts”) begin to grow directly from the tree trunk as growth at the outermost branches slows. There is some indication that trees become more vulnerable to fungus and disease with old age, but for the most part, old trees succumb to the mechanical hazards of excess size. The very ability to continue growing that offers them the possibility of “reverse aging” over so many decades proves in the end to be their downfall.
FOREVER YOUNG: The “immortal jellyfish” returns to a polyp stage after spawning. Then it grows up again. Yiming Chen
Though it doesn’t enroll in kindergarten at age 65, the immortal medusoid Turritopsis nutricula achieved its 15 minutes of fame when it was hailed as “the immortal jellyfish” in science news articles of 2010. The adult Turritopsis has inherited a neat trick: After spawning its polyps, it regresses back to a polyp, beginning its life anew. This is accomplished by turning adult cells back into stem cells, going against the usual developmental direction from stem cells to differentiated cells—in essence driving backward down a one-way developmental street. Headlines called Turritopsis the “Benjamin Button of the Sea.”
Dermestid beetles (Trogoderma glabrum) perform a similar trick, but only when starved. As they play life out on a carcass in the woods, the beetles go through six different larval stages in succession, looking like a grub, and then a millipede, and then a water glider before ending up as a six-legged beetle. A pair of entomologists working at the University of Wisconsin in 1972 isolated the sixth-stage larvae (when they were just ready to become adults) in test tubes and discovered that without food, they regressed to stage-five larvae. If they were deprived of food for many days, they would actually shrink and regress backward through the stages until they looked like newly hatched maggots. Then, if feeding was resumed, they would go forward again through the developmental stages and become adults with normal life spans. They found they were able to repeat the cycle over and over again, allowing them to grow to stage six and then starving them back down to stage one, thereby extending their life spans from eight weeks to more than two years.
Hydras are radially symmetrical invertebrates, each with a mouth on a stalk, surrounded by tentacles, which grow back when cut off—like the many-headed monster of Greek mythology for which they are named. They have been studied for four years at a time, starting with specimens of various ages collected in the wild, and they don’t seem to die on their own or to become more vulnerable to predators or disease. In the human body, certain cells, such as blood cells, skin, and those of the stomach lining, slough off and regenerate continuously. The hydra’s whole body is like this, regenerating itself from stem cell bedrock every few days. Some cells slough off and die others, when large enough, grow into hydra clones that bud from the stalk-body to strike out on their own. This is an ancient style of reproduction, making do without sex. For the hydra, sex is optional—an occasional indulgence.
One recent article claims that the hydra does indeed grow older, and it shows it by slowing its rate of cloning. The author suggests that perhaps clones inherit their parents’ age. The hypothesis is that only sexual reproduction resets the aging clock. If this is true, then the hydra’s style of aging is a throwback to protists, ancestral microbes more complex than bacteria—some of which have a limited life span, being able to divide only so many times until they run out of reproductive gas—unless they are jumpstarted by exchanging genes (a kind of protist version of sex), which resets their aging clock. Amoebas and microbes of the genus Paramecium are examples of these protists, single cells in a vast lineage that has anciently radiated into over 100,000 species and includes all the seaweeds, slime molds, and ciliates and other organisms that do not belong to the animal, fungal, plant, or bacteria kingdoms.
Queen bees and worker bees have the same genes but very different life spans. In the case of the queen bee, royal jelly switches off aging. When a new hive begins, nurse bees select—arbitrarily so far as we can tell—one larva to be feted with the liquid diet of royalty. Some physiologically active chemical ambrosia in the royal jelly triggers the lucky bee to grow into a queen instead of a worker. The royal jelly confers upon the queen the overdeveloped gonads that give her a distinctive size and shape. The queen makes one flight at the beginning of her career, during which she might mate with a dozen different drones, storing their sperm for years to come.
Weighted down with eggs, the full-grown queen, too heavy to fly, becomes a reproducing machine: she lays at a prodigious rate of about 2,000 per day, more than her entire body weight. Of course, such reproductive regality requires a suite of specialized workers to feed her, remove her waste, and transmit her pheromones (chemical signals) to the rest of the hive.
Worker bees live but a few weeks and then die of old age. And they don’t just wear out from broken body parts, the rough-and-tumble worlds through which they fly. We know this because their survival follows a familiar mathematical form, called the gompertz curve, the characteristic tailing of survival, typical for humans and many other animals, indicating aging. Meanwhile, queen bees, though their genes are identical to those of the workers, show no symptoms of senescence. They can live and lay for years and sometimes, if the hive is healthy and stable, for decades. They are ageless wonders. The queen dies after running out of the sperm she received during her nuptial flight. At that point, she may continue to lay eggs, but they come out unfertilized and can only grow into stingless drones. Then, the same workers that formerly attended her assassinate the depleted queen. They swarm about her, stinging her to death.
Post-Reproductive Life Spans
Why is there a menopause? We care for our young and our extended families, and our devotion continues after our children have grown and become parents themselves. Hence, the standard explanation for life that continues after fertility ends is called the “grandmother hypothesis.” Women have a genetic interest in seeing their grandchildren grow up healthy. Maybe at age 60 they can contribute more to their own genetic legacy by caring for their grandchildren than by having more babies of their own. This is a hypothesis that sounds reasonable, at least for humans, but a number of demographic researchers have found that when they do the numbers, it’s hard to make it work.
Whales and elephants are also examples of organisms who outlive their fertility. They are social animals, too. Perhaps they are more important to their grandchildren than we know. But in the chart, there are other animals that go right on living after their fertility has ended. These include guppies, water fleas, roundworms, and bdelloid rotifers, all of which make deadbeat dads look like Mary Poppins. All these animals lay eggs, and that’s it. None of them lifts a wing or a fin to care for their young, let alone their grandchildren. Yet modern evolutionary theory says that there is no natural selection to keep them alive, and thus we should expect them to be kaput.
In 2011, Charles Goodnight and I had an idea about how post-reproductive life span might evolve, an idea that sounds pretty unlikely in the abstract, but when we did the numbers, it actually panned out. An older, “retired” segment of the population, we argued, serves to keep the population stable over cycles of feast and famine. When times are good, they eat the excess food and help prevent population overshoot. When food is scarce, they are the first to die.
S tyles of aging in nature are just about as diverse as they can be, which suggests that nature is able to turn aging on and off at will. With this in mind, we may be forgiven for regarding theories that explain why aging must exist with extreme skepticism. Whatever our theory of aging turns out to be, it had better make room for plasticity, diversity, and exceptions.
Theoretical-biologist Josh Mitteldorf has a Ph.D. from the University of Pennsylvania. He runs the website AgingAdvice.org, and writes a weekly column for ScienceBlog.com. Mitteldorf has had visiting research and teaching positions at various universities including MIT, Harvard, and Berkeley.
Dorion Sagan is a celebrated writer, ecological philosopher, and theorist. His essays, articles, and book reviews have appeared in Natural History, Smithsonian, Wired, New Scientist, and The New York Times, among others.
1. Jones, O.R., et al., Diversity of ageing across the tree of life. Nature 505, 169–173 (2014).
Excerpted from Cracking the Aging Code by Josh Mitteldorf and Dorion Sagan. Copyright © by the authors and reprinted by permission of Flatiron Books, a division of Holtzbrinck Publishers Ltd.
Cognitive decline with age is normal, routine, but not inevitable
If you forget where you put your car keys and you can&rsquot seem to remember things as well as you used to, the problem may well be with the GluN2B subunits in your NMDA receptors.
And don&rsquot be surprised if by tomorrow you can&rsquot remember the name of those darned subunits.
They help you remember things, but you&rsquove been losing them almost since the day you were born, and it&rsquos only going to get worse. An old adult may have only half as many of them as a younger person.
Research on these biochemical processes in the Linus Pauling Institute at Oregon State University is making it clear that cognitive decline with age is a natural part of life, and scientists are tracking the problem down to highly specific components of the brain. Separate from some more serious problems like dementia and Alzheimer&rsquos disease, virtually everyone loses memory-making and cognitive abilities as they age. The process is well under way by the age of 40 and picks up speed after that.
But of considerable interest: It may not have to be that way.
&ldquoThese are biological processes, and once we fully understand what is going on, we may be able to slow or prevent it,&rdquo said Kathy Magnusson, a neuroscientist in the OSU Department of Biomedical Sciences, College of Veterinary Medicine, and professor in the Linus Pauling Institute. &ldquoThere may be ways to influence it with diet, health habits, continued mental activity or even drugs.&rdquo
The processes are complex. In a study just published in the Journal of Neuroscience, researchers found that one protein that stabilizes receptors in a young animal &ndash a good thing conducive to learning and memory &ndash can have just the opposite effect if there&rsquos too much of it in an older animal.
But complexity aside, progress is being made. In recent research, supported by the National Institutes of Health, OSU scientists used a genetic therapy in laboratory mice, in which a virus helped carry complementary DNA into appropriate cells and restored some GluN2B subunits. Tests showed that it helped mice improve their memory and cognitive ability.
The NMDA receptor has been known of for decades, Magnusson said. It plays a role in memory and learning but isn&rsquot active all the time &ndash it takes a fairly strong stimulus of some type to turn it on and allow you to remember something. The routine of getting dressed in the morning is ignored and quickly lost to the fog of time, but the day you had an auto accident earns a permanent etching in your memory.
Within the NMDA receptor are various subunits, and Magnusson said that research keeps pointing back to the GluN2B subunit as one of the most important. Infants and children have lots of them, and as a result are like a sponge in soaking up memories and learning new things. But they gradually dwindle in number with age, and it also appears the ones that are left work less efficiently.
&ldquoYou can still learn new things and make new memories when you are older, but it&rsquos not as easy,&rdquo Magnusson said. &ldquoFewer messages get through, fewer connections get made, and your brain has to work harder.&rdquo
Until more specific help is available, she said, some of the best advice for maintaining cognitive function is to keep using your brain. Break old habits, do things different ways. Get physical exercise, maintain a good diet and ensure social interaction. Such activities help keep these &ldquosubunits&rdquo active and functioning.
Gene therapy such as that already used in mice would probably be a last choice for humans, rather than a first option, Magnusson said. Dietary or drug options would be explored first.
&ldquoThe one thing that does seem fairly clear is that cognitive decline is not inevitable,&rdquo she said. &ldquoIt&rsquos biological, we&rsquore finding out why it happens, and it appears there are ways we might be able to slow or stop it, perhaps repair the NMDA receptors. If we can determine how to do that without harm, we will.&rdquo
Until fairly recently, little information existed about how long prehistoric people lived. Having access to too few fossilized human remains made it difficult for historians to estimate the demographics of any population.
Anthropology professors Rachel Caspari and Sang-Hee Lee, of Central Michigan University and the University of California at Riverside, respectively, chose instead to analyze the relative ages of skeletons found in archeological digs in eastern and southern Africa, Europe, and elsewhere.
After comparing the proportion of those who died young with those who died at an older age, the team concluded that longevity only began to significantly increase—that is, past the age of 30 or so—about 30,000 years ago, which is quite late in the span of human evolution.
In an article published in 2011 in Scientific American, Caspari calls the shift the “evolution of grandparents," as it marks the first time in human history that three generations might have co-existed.
The new biology of ageing
Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.
The increase in life expectancy in human populations worldwide is a triumph of biomedical research. Survival rates started to increase in the mid-nineteenth century, because of improvements in public health, particularly clean water, immunization and antibiotics, and also because of other improvements in lifestyle such as better housing. The rate of increase in life expectancy in most countries does not yet show any sign of slowing and, indeed, is greatest in older age classes we cannot yet see what any intrinsic limit to human life expectancy will be (Wilmoth 2000 Oeppen & Vaupel 2002).
For a given age, health now is better than it was 150 years ago, but this welcome change is also producing great challenges. Many of these are socio-economic, concerning issues such as work force participation and affordability of pension schemes. Paradoxically, there is also a major medical problem. The improvement in individual health means that larger numbers of individuals reach older ages, and hence live long enough to suffer from ageing-related disease and loss of function. All of the major killer diseases, including cardiovascular disease, cancer and dementia, are strongly age related. The predominant burden of ill-health is now falling on the older section of the population and, both for health benefits to ageing individuals and economic benefits to the societies in which they live, we urgently need to discover means of improving health during ageing. Fortunately, major scientific opportunities have opened up in research into ageing and bring with them the enticing prospect of a broad-spectrum, preventative, medicine for diseases of ageing. However, taking the fruits of these scientific discoveries to the ageing human population may not be straightforward.
From the biological standpoint, the major features of ageing are an intrinsic decline in function during adulthood, leading to a drop in fecundity and increased likelihood of death (Finch 1990). Ageing is not inevitable and, indeed, some organisms seem not to age at all or to do so very slowly. Some even show an increase in fecundity or survival rate over at least part of adulthood. Ageing is particularly apparent in organisms where growth is completed before reproduction commences, such as insects, birds and many mammals, including humans (Vaupel et al. 2004 Baudisch 2005). The major laboratory model organisms used for research into ageing, namely budding yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster and the mouse Mus musculus, all fall into this category and, in this sense at least, are good models for human ageing.
The phenotypes associated with ageing have been best studied in humans and are complex (Martin 2002). Within single tissues, multiple types of damage and pathology increase in incidence with age, and the spectrum of changes differs between tissues. The precise phenotypes of ageing are also notably variable between individuals (Finch & Kirkwood 1999). This complexity and variability have led to a picture of the ageing process as intractable, for both experimental analysis and medical intervention. Indeed, it could be concluded that there is no single ageing process rather, during ageing, a large number of independent and stochastic processes of damage accumulation occur in parallel, with little or no common causality. Amelioration of the impact of one type of ageing-related damage would, if this scenario is correct, leave the majority unaffected and would hence have little impact on overall ageing-related decline. This view of ageing permeates medicine to the present day. Geriatrics is largely a primary care medical speciality, with little input from basic and clinical research, unlike specific ageing-related diseases such as cancer, cardiovascular disease and neurodegeneration, which are all associated with sizeable and well-funded research communities. Specific diseases of ageing are generally viewed as medically tractable, unlike the ageing process itself.
The idea that ageing is difficult to modify has until recently been reinforced by work on its evolution. Evolutionary biologists have long been intrigued by ageing, because it is a deleterious trait, but it nonetheless shows great diversity in the natural world. After various ideas of a possible benefit of ageing to family groups or whole species were largely discredited (Kirkwood & Cremer 1982), the key insight came with the realization that, because of extrinsic causes of mortality such as disease, predation and accidents, the force of natural selection weakens for older age classes, because fewer individuals succeed in reaching them (Haldane 1941 Medawar 1946, 1952). A substantial body of theoretical analysis, experimentation and comparative work led to the conclusion that ageing can hence evolve as a side effect, either of pressure of new mutations that reduce fecundity or survival probability later in life or of mutations that have beneficial effects in the young (Medawar 1952 Williams 1957 Hamilton 1966 Hughes & Reynolds 2005 Partridge & Gems 2006 Moorad & Promislow 2008). As far as we know, no genes have evolved to cause ageing. Unlike development, there is no well-oiled hierarchy of genetic regulation to ensure that ageing happens in the right tissues and at the right times. Instead, it is an unregulated side effect of the failure of natural selection to maintain function at the later ages that few individuals reach in nature (Partridge & Gems 2002a). These theoretical and practical insights have led to the conclusion that ageing is likely to be a highly polygenic trait, since many genes are involved in assurance of survival during adulthood and in promoting fecundity.
The complexity of the ageing phenotype and the realization that it is an evolutionary side effect, rather than an adaptive process, led to the widespread assumption that mutations in single genes were unlikely to be capable of slowing down ageing. Furthermore, it seemed improbable that mechanisms of ageing would be the same in different kinds of organisms. If different human tissues acquire such different forms of damage and pathology during ageing, presumably as a result of the different types of insults of daily living that they encounter then, by the same token, organisms with very different life styles would be expected to encounter different sources of damage (Partridge & Gems 2002b).
2. Single-gene mutations that extend the lifespan of laboratory animals
Perhaps the single most important advance in ageing research in recent years has been discovery of mutations in single genes that extend the lifespan of laboratory animals. They first came to light as a result of a systematic chemical mutagenesis screen for lifespan-extending mutations in C. elegans (Klass 1983). Subsequent work with these mutations (Friedman & Johnson 1988), and further screening (Kenyon et al. 1993), revealed that it was possible to double the lifespan of the worm with a mutation in a single gene. Furthermore, rather than solely prolonging the moribund period at the end of the life, the mutations caused the worms to remain healthy and youthful for longer (Kenyon et al. 1993). The mutated genes were discovered to encode components of an invertebrate insulin/insulin-like growth-factor-like signalling (IIS) pathway (Kimura et al. 1997 Lin et al. 1997 Ogg et al. 1997). These findings came as a considerable surprise, because a signalling pathway previously associated with control of growth and metabolism in mammals now turned out to play a role in determination of lifespan in a distantly related invertebrate.
Mutations with similar effects on lifespan were soon discovered in other model organisms. For instance, a similar screening effort in yeast led to the discovery that over-expression of a protein deacetylase, SIR2, extended replicative lifespan (Sinclair & Guarente 1997 Kaeberlein et al. 1999), while mutations in methuselah in Drosophila increased fly lifespan (Lin Seroude & Benzer 1998). Likewise, in the mouse, mutations in genes encoding transcription factors involved in the development of the pituitary gland resulted in long-lived dwarf mice (Brown-Borg et al. 1996). By the late 1990s, it was firmly established that lifespan of these model organisms could indeed be extended by mutations in single genes.
It had also been known since the 1930s that an environmental intervention, dietary restriction (DR), could produce substantial increases in lifespan in laboratory rodents (McCay et al. 1935). Although the exact mechanisms at work still await full elucidation, detailed study of DR rodents has demonstrated a broad-spectrum improvement in health and a delay in or amelioration of the impact of a wide range of ageing-related diseases (Masoro 2005, 2006). For instance, the animals are protected against cancer, cataract, diabetes, motor decline, osteoporosis and nephropathy (Weindruch & Walford 1988). These findings suggested that, in principle, multiple aspects of the ageing phenotype could be simultaneously ameliorated by a single intervention, albeit, in the case of DR, a complex one.
3. Evolutionary conservation
The ultimate aim of biomedical research into ageing with animals is to improve the health of the older section of human populations. Laboratory model organisms have been key to understanding many other aspects of human biology. Embryonic development, the cell cycle, the functioning of the nervous system, cellular metabolism and many other processes have often been investigated by proceeding from simpler organisms to more complex ones. This process works because of evolutionary conservation of genes and their functions over the large evolutionary distances involved. Indeed, it is often possible to introduce a human gene into yeast or Drosophila and find that it functions quite normally there. However, because ageing is not an adaptive trait and because different kinds of organisms are exposed to different kinds of stress and damage, there has been a good reason to doubt that this kind of evolutionary conservation will apply to the ageing process.
DR extends lifespan not only in rodents but also in a wide range of distantly related organisms, including yeast (Jiang et al. 2000 Lin et al. 2000), C. elegans (Klass 1977 Lakowski & Hekimi 1998 Greer et al. 2007 Kennedy et al. 2007 Smith et al. 2008a) and Drosophila (Chippindale et al. 1993 Chapman & Partridge 1996). Indeed recent work has demonstrated that DR increases lifespan in rhesus monkeys (Holloszy & Fontana 2007 Mattison et al. 2007 Colman et al. 2009) and short-term DR can produce improvements in function in humans (e.g. Holloszy & Fontana 2007). Because the details of the mechanisms by which DR extends lifespan are not fully elucidated for any organism, it is not clear whether this is a case of evolutionary conservation or whether instead there has been evolutionary convergence (Mair & Dillin 2008).
It was originally suspected that extension of lifespan by reduced IIS might turn out to be a worm peculiarity. This was because mutations in genes in the IIS pathway can also cause the worms to enter a type of developmental arrest (dauer), normally seen only in response to low food or crowding (Riddle & Albert 1997). Dauer larvae are long lived, and the long life of IIS mutant adult worms could therefore have been a result of re-expression in the adult of the genes that make the dauer larva long lived (Kenyon et al. 1993), a speculation confirmed by studies of gene expression (McElwee et al.2003, 2004). Most organisms do not undergo this type of developmental arrest and might therefore lack the mechanisms for long life seen in dauer larvae. However, an important recent discovery has been that the IIS pathway has an evolutionarily conserved role in determining longevity mechanisms of ageing therefore are, at least to some extent, ‘public’ or shared (Partridge & Gems 2002b). Remarkably, mutations in the single Drosophila insulin receptor (Tatar et al. 2001) and insulin receptor substrate (Clancy et al. 2001) proved to extend lifespan in the fly. Furthermore, mutations in the genes encoding both the insulin (Bluher et al. 2003) and Igf-1 receptor (Holzenberger et al. 2003) extended lifespan in the mouse. Subsequent work with all three organisms has amply confirmed the evolutionarily conserved role of this signalling pathway (Russell & Kahn 2007 Piper et al. 2008 Taguchi & White 2008). Early evidence from population–genetic association studies has also started to implicate the pathway in determination of human lifespan (Mooijaart et al. 2005 Kuningas et al. 2007 Willcox et al. 2008).
Evidence for evolutionary conservation of genetic determinants of lifespan is at present strongest for the IIS pathway, but others are likely to lengthen the list. For instance, the effect of elevated expression of SIR2 in yeast appears to be conserved in C. elegans (Tissenbaum & Guarente 2001) and Drosophila (Rogina & Helfand 2004), and mutations in genes encoding components of the target of rapamycin (TOR) pathway also extend the lifespan in all four organisms (Jia et al. 2004 Kapahi et al. 2004 Kaeberlein et al. 2005 Hansen et al. 2007 Pan et al. 2007 Sheaffer et al. 2008 Smith et al. 2008b Harrison et al. 2009). Sufficient single-gene mutations that extend lifespan in yeast and C. elegans have now been identified to allow a quantitative estimate of the degree of evolutionary conservation of genetic modifiers of ageing between these two organisms (Smith et al. 2008b). In C. elegans, loss of function of a set of approximately 276 genes, or altered function of their protein products, has proved to extend lifespan. A set of 103 yeast orthologues of 78 of these 276 worm genes could be identified on the basis of sequence similarity, and deletion of 76 of these resulted in viable yeast strains. Eleven of the 76 were long lived, a proportion 4.3 times higher than would be expected from deletion of the same number of randomly selected yeast genes. Many of the genes with a conserved role in ageing in these two organisms are involved in protein synthesis (Smith et al. 2008b), a process whose importance to ageing has recently been demonstrated by experimental studies in C. elegans (Hansen et al. 2007 Pan et al. 2007). This strong signal of evolutionary conservation between these two distantly related organisms suggests that future studies of the role of protein synthesis in ageing in the fruitfly and the mouse would pay dividends.
Although there is abundant evidence for an evolutionarily conserved role for IIS and other pathways in determination of lifespan, it remains to be seen how deep that conservation penetrates. Even at the level of signalling mechanisms, there may be considerable variation between different organisms as is implied, for instance, by the presence of much larger numbers of insulin ligands in the worm (38) and the fly (7) than in mammals. In addition, similar changes in signalling in different organisms may have very different outcomes because of differences in structure and physiology. Of particular importance for IIS, insulin resistance and failure in insulin production can result in diabetes in mammals, with its consequent vascular damage, while the invertebrates, with their open circulatory systems, can probably better tolerate elevated blood sugar. Only a narrow range of alterations in IIS may therefore increase mammalian lifespan. There is some evidence for evolutionary conservation of the biochemical mechanisms by which altered IIS extends lifespan in different organisms. For instance, profiling of gene expression in long-lived, IIS mutant worms, flies and mice showed increased expression of genes encoding components of phase 1 and 2 detoxification pathway, important in the elimination of lipophilic endobiotics, xenobiotics and drugs (McElwee et al. 2007 Sykiotis & Bohmann 2008 Tullet et al. 2008). Subsequent work with a key transcriptional regulator of the pathway has demonstrated experimentally that increasing its activity can increase lifespan in both C. elegans and Drosophila (McElwee et al. 2007 Sykiotis & Bohmann 2008 Tullet et al. 2008). Cellular detoxification may therefore be an important process for protection against the effects of ageing in all three organisms, although whether the toxins involved are the same or different remains to be determined.
So far we have only scratched the surface of the mechanisms at work in lifespan extension. Nonetheless, these new findings have opened up the promise of a major scientific opportunity, to use the invertebrates and the mouse to understand human ageing, exploiting the full range of analytical tools available in the model organisms.
4. Risk and damage
Slowing down ageing is not the only means by which lifespan can be extended. The ageing process is characterized by a decline in function with advancing age during adulthood the state of the organisms progressively worsens. One might therefore expect that an intervention that extended lifespan by amelioration of the ageing process would do so by slowing down the rate at which state worsens with age (Finch 1990). A simple and direct way of assessing the state of a population is to measure mortality rate, which is, to a first approximation, the proportion of individuals that enter each age class that die during it. Mortality rates generally show a roughly exponential increase with age in humans and the laboratory model organisms and can hence be described in terms of two important parameters: the initial, baseline mortality rate, which is age independent, and the rate at which mortality rate increases with age (Finch 1990 Pletcher et al. 2000). Interventions, genetic and environmental, that increase lifespan can do so by decreasing either or both of these parameters (Pletcher et al. 2000). A reduction in the slope of a mortality trajectory is what would be expected if lifespan were increased by a reduction in the rate of ageing itself (Finch 1990).
One intervention that clearly can slow down the rate of ageing is lowered temperature for ectotherms. In Drosophila, lowered temperature increases lifespan entirely by lowering the slope of the mortality trajectory, with no effect on the initial mortality rate (Mair et al. 2003). These flies are too small to thermoregulate and are thus forced to adopt ambient temperature. Lowering of the slope of the mortality trajectory in cooler environments is consistent with the idea that lowered temperature decreases the rate of most or all molecular processes in the organism, including the rate of ageing. In support of this view, when flies are switched between temperatures, the subsequent slope of the mortality trajectory immediately changes to that characteristic of flies kept permanently in the new thermal regime (Mair et al. 2003). The flies therefore bear the permanent imprint of their thermal history, with warmer temperatures leading to the accumulation of a higher level of irreversible damage, and no acute effect of temperature on mortality rate. Lowered temperature thus decreases the rate of ageing in Drosophila and provides a useful benchmark for an intervention that does so.
Rather than decreasing the rate of ageing, the increase in lifespan in industrialized human societies has occurred by a reduction in baseline mortality rates, with no reduction in the slope of the mortality trajectory (Wilmoth 2000). This suggests that overall health, at all ages, has improved, but that the underlying process of accumulation of ageing-related damage has not been ameliorated. This finding leaves open the question of the time course of these effects. For instance, events early in life or even in utero could have a lifelong impact on health, and there could also be more acute effects of recent and current environments. To measure such timing effects, it is necessary to compare individuals with currently similar circumstances but different past environments, and vice versa.
Interestingly, DR can have a similar effect on mortality trajectories to that associated with the increase in human lifespan expectancy DR extends life in Drosophila entirely by reducing the initial mortality rate with no lowering of its slope (Pletcher et al. 2000). Similar findings have been reported for DR in mice (Weindruch et al. 1986 Hursting et al. 1994), and for one form of DR in C. elegans (Smith et al. 2008a), suggesting that, in these three organisms at least, DR may not slow down the rate of ageing and may instead increase lifespan through a different mechanism. Indeed, experimental reversal of the nutritional status of flies has shown that the effect of DR on mortality rate is acute. Later onset DR leads, within 48 h, to a switch in subsequent mortality rates to those of permanently DR flies (Mair et al. 2003). Likewise, previously DR flies that are switched to full feeding at later ages show a rapid increase in mortality rates to those characteristic of flies that are permanently fully fed. DR and fully fed flies thus age at the same rate, and DR instead extends lifespan by reducing the acute risk of death.
There is little information on the timing of the effects of single-gene mutations on mortality rate. In C. elegans, switches in IIS status using double stranded RNA interference have shown that the pathway acts specifically during adulthood to determine adult survival (Dillin Crawford & Kenyon 2002), but more detailed timing information is not yet available. In Drosophila, an inducible system for gene expression was used to show that, at least up to a month of adult age, the IIS pathway acts acutely to determine mortality rate, similar to DR (Giannakou et al. 2007). It will be important to determine whether this kind of acute effect on mortality rate applies to other pathways that determine lifespan and, in particular, whether it extends to mammals. But it is already clear that, in principle, lifespan can be extended by making the animal less likely to die of the damage that it has accumulated, rather than by reducing the accumulation of damage.
5. Ageing and ageing-related diseases
It has long been known that DR in rodents reduces the impact of a wide range of ageing-related diseases, and it has also been shown to reduce the impact of proteotoxicity in C. elegans (Steinkraus et al. 2008). Because the single-gene mutations that extend lifespan have only been discovered recently, less information is available, but already it seems that aspects of function and health during ageing are improved. For instance, associative learning is more strongly maintained at later ages in long-lived IIS mutants worms (Murakami et al. 2005), while locomotor function is better maintained during ageing in long-lived IIS mutant flies (Martin & Grotewiel 2006). Loss of the insulin receptor substrate 1 in the mouse also protects against loss of glucose homeostasis, immune and motor function and reduces the impact of osteoporosis, cataract and ulcerative dermatitis (Selman et al. 2008). As well as maintaining function and health during ageing, lifespan-extending mutations can protect against the pathology associated with specific genetic models of ageing-related disease. For instance, recent work with C. elegans has revealed that mutations in IIS that increase lifespan can reduce the pathology associated with genetic models of cancer (Pinkston et al. 2006 Pinkston-Gosse & Kenyon 2007) and of proteotoxicity-induced neurodegeneration (Cohen et al. 2006 Pinkston et al. 2006 Steinkraus et al. 2008). Furthermore, mutations in IIS in the mouse can protect against the pathology associated with specific genetic models of Alzheimer's disease (Freude et al. 2009 Killick et al. 2009). The indications are, therefore, that these interventions can produce an improvement in health and function in diverse tissue systems and reduce the impact of ageing-related diseases with diverse aetiology (Butler et al. 2008).
The implication of these findings is that protection against the ageing process results in protection against diverse, ageing-related diseases. The ageing process itself is acting as the major risk factor for these conditions. This realization leads in turn to the conclusion that there is an underlying commonality in the aetiology of these ageing-related diseases, despite their diverse manifestations. It is early days yet, and a great deal more work needs to be done to understand exactly how the ageing process increases vulnerability to these diseases. We need also to understand how transition into loss of function and disease occurs, and how a single environmental intervention or gene mutation can have such broad-spectrum effects. A key challenge in the biology of ageing, and one that is increasingly being recognized, is to understand how events at different levels of organization contribute to loss of function during organismal ageing and to eventual death (Kirkwood 2008 Murphy & Partridge 2008). Presumably, in a complex chain of events, damage to macromolecules and organelles causes decline in cellular function and cell loss, which in turn compromise the function of tissues. Dysfunctional tissues could in turn act systemically to cause stress and eventual damage to other tissues, which could to some extend cause a correlation in the rate of ageing of different parts of the body within an individual. Many of these key changes may be susceptible to acute intervention, similar to the effects of DR in the invertebrate model organisms. At some point, irreversibility must enter the system, because of the emergence of lethal, ageing-related disease that cannot be rescued by the intervention (Partridge Pletcher & Mair 2005b). Identifying, experimentally investigating and modelling these temporal changes and their dynamics will require considerable effort, and in the near future much more experimental work will be needed to bring understanding of these systems to a level of maturity where productive modelling will be possible.
6. Will lifespan extension in laboratory model organisms be relevant to human ageing?
The findings from the model organisms have a clear, potential message for the medical treatment of ageing-related diseases (Butler et al. 2008). At present, these diseases are treated piecemeal by different medical specialists, because they are regarded as separate medical problems. Patients themselves generally visit a clinician because they have a specific medical problem, not because they are old. However, if in humans, also, protection against the effect of ageing can delay or ameliorate diverse ageing-related diseases, then a quite different approach to the health of older people would pay dividends. A broad-spectrum, preventative approach would be required, with individuals who reached a certain age being treated even in the absence of any ageing-related disease. Furthermore, if the effects of a beneficial intervention were acute, as has occurred in some of the animal models, then it would need to be applied for the rest of life. Clinical trials would also need to be conducted for a protracted period. All of these features would pose significant obstacles to translating the findings from basic science into drug development and clinical practice. However, if the findings from the animal models turn out to apply to humans, then a major opportunity could be missed. What, then, is the likelihood that evolutionary conservation of the mechanisms will extend to our own species?
There are some obvious questions about lifespan extension in animal models that have a bearing on likely relevance to humans. If these single gene mutations can produce such broad-spectrum benefits to health, then why is the mutant not the wild-type? These mutants must have side effects that mean that they are not the fittest genotype in the wild. Some mutants that extend lifespan clearly delay or reduce fecundity, as does DR (Partridge et al. 2005a). However, it is also clear that, at least in the laboratory, impaired fecundity is not necessary for extension of lifespan by some single-gene mutations (Partridge et al. 2005a), although some claims that this is the case may have been based on failing to measure all aspects of fecundity or doing so in benign circumstances (Rogina et al. 2000 Walker et al. 2000 Marden et al. 2003 Jenkins et al. 2004). Nature is in general a more exacting place than the laboratory, where the animals are kept largely free of pathogens, have an abundant and highly accessible food supply and are kept largely free of competition with conspecifics. However, many of these considerations apply also to humans in developed countries. It will be important to evaluate what are the negative effects of single-gene mutations that make them disadvantageous under natural circumstances, to understand how important these might be for humans. It should also be borne in mind that medical interventions into ageing are likely to be applied only later in the lifespan, when some of the negative side effects may no longer be relevant, and it has already been demonstrated that administration of a TOR inhibitor, rapamycin, later in life in mice can extend the lifespan (Harrison et al. 2009). The prospects that the findings from the laboratory will prove to be of medical relevance to humans therefore look promising.
Humans are, obviously, much longer lived than any of the laboratory model organisms. This could have a bearing on the extent to which interventions could ameliorate the effects of ageing, or not. It is notable that many of the genes that have so far come to light as affecting longevity in the laboratory are involved in nutrient sensing pathways, which contribute to matching the growth and reproductive rate of the animals to their nutritional status. Human growth and reproduction respond to nutrients, but not to such an extent as do those of the laboratory model organisms, which are all subject to boom and bust conditions in nature. However, even if human lifespan is not as plastic as that of laboratory animals, the same may not be true for ageing-related disease. The aim of this research is to improve human health during ageing, not to extend lifespan per se, and it remains to be seen to what extent this is going to be possible.