Rejuvenation is a medical discipline focused on the practical reversal of the aging process.
Rejuvenation is distinct from life extension.
Life extension strategies often study the causes of aging and try to
oppose those causes in order to slow aging. Rejuvenation is the reversal
of aging and thus requires a different strategy, namely repair of the
damage that is associated with aging or replacement of damaged tissue
with new tissue. Rejuvenation can be a means of life extension, but most
life extension strategies do not involve rejuvenation.
Historical and cultural background
Various myths tell the stories about the quest for rejuvenation. It was believed that magic or intervention of a supernatural
power can bring back youth and many mythical adventurers set out on a
journey to do that, for themselves, their relatives or some authority
that sent them anonymously.
An ancient Chinese emperor actually sent out ships of young men
and women to find a pearl that would rejuvenate him. This led to a myth
among modern Chinese that Japan was founded by these people.
In some religions, people were to be rejuvenated after death prior to placing them in heaven.
The stories continued well into the 16th century. The Spanish explorer Juan Ponce de León led an expedition around the Caribbean islands and into Florida to find the Fountain of Youth.
Led by the rumors, the expedition continued the search and many
perished. The Fountain was nowhere to be found as locals were unaware of
its exact location.
Since the emergence of philosophy, sages and self-proclaimed wizards always made enormous efforts to find the secret of youth, both for themselves and for their noble patrons and sponsors. It was widely believed that some potions may restore the youth.
Another commonly cited approach was attempting to transfer the essence of youth from young people to old. Some examples of this approach were sleeping with virgins or children (sometimes literally sleeping, not necessarily having sex).
The quest for rejuvenation reached its height with alchemy. All around Europe, and also beyond, alchemists were looking for the Philosopher's Stone,
the mythical substance that, as it was believed, could not only turn
lead into gold, but also prolong life and restore youth. Although the
set goal was not achieved, alchemy paved the way to the scientific method and so to the medical advances of today.
Serge Abrahamovitch Voronoff
was a French surgeon born in Russia who gained fame for his technique
of grafting monkey testicle tissue on to the testicles of men while
working in France in the 1920s and 1930s. This was one of the first
medically accepted rejuvenation therapies (before he was proved to be
wrong around 1930–1940). The technique brought him a great deal of
money, although he was already independently wealthy. As his work fell
out of favor, he went from being a highly respected surgeon to a subject
of ridicule. By the early 1930s, over 500 men had been treated in
France by his rejuvenation technique, and thousands more around the
world, such as in a special clinic set up in Algiers. Noteworthy people who had the surgery included Harold McCormick, chairman of the board of International Harvester Company, and the aging premier of Turkey.
Swiss doctor Paul Niehans,
who was one of the fathers of cellular therapy, developed in 1931–1949
years the so-called Fresh cell therapy. Fresh cell therapy is mainly the
use of live animal embryo organs cells which are injected into the
patient with the purpose of achieving a revitalizing effect. These cells
are generally extracted from sheep’s fetuses
because in comparison to other animals, like pigs, rabbits and cows,
sheep are clean animals and rarely contract diseases. Of course animal
cells are not able to be included in human tissue, but they can secrete
factors for rejuvenating. That's why this rejuvenation technology,
despite the harsh criticism is practiced to this day.
Rejuvenation technology and its effects on individuals and society have long been a subject of science fiction. The Misspent Youth and Commonwealth Saga by Peter F. Hamilton
are among the most well known examples of this, dealing with the short-
and long-term effects of a near perfect 80-year-old to 20-year-old body
change with mind intact. The less perfect rejuvenation featured in the Mars trilogy by Kim Stanley Robinson results in long-term memory loss and sheer boredom that comes with extreme age. The post-mortal characters in the Revelation Space
series have long-term or essentially infinite lifespans, and sheer
boredom induces them to undertake activities of extreme risk.
There have been many experiments which have been shown to increase the maximum life span of laboratory animals, thereby achieving life extension. A few experimental methods such as replacing hormones to youthful levels have had considerable success in partially rejuvenating laboratory
animals and humans. A recent experiment involved breeding genetically
manipulated mice that lacked an enzyme called telomerase, causing the
mice to age prematurely and suffer ailments. When the mice were given
injections to reactivate the enzyme, it repaired the damaged tissues and
reversed the signs of aging. There are at least eight important hormones that decline with age: 1. human growth hormone (HGH); 2. the sexual hormones: testosterone or oestrogen/progesterone; 3. erythropoietin (EPO); 4. insulin; 5. DHEA;
6. melatonin; 7. thyroid; 8. pregnenolone. In theory, if all or some of
these hormones are replaced, the body will respond to them as it did
when it was younger, thus repairing and restoring many body functions.
In line with this, recent experiments show that heterochronic parabiosis,
i.e. connecting the circulatory systems of young and old animal, leads
to the rejuvenation of the old animal, including restoration of proper
stem cell function. Similar experiments show that grafting old muscles
into young hosts leads to their complete restoration, whereas grafting
young muscles into old hosts does not. These experiments show that aging
is mediated by systemic environment, rather than being an intrinsic
cell property. Clinical trials based on transfusion of young blood were scheduled to begin in 2014. Another intervention that is gaining popularity is epigenetic reprogramming. Through the use of Yamanaka factors, aged cells can revert to a younger state.
Most attempts at genetic repair have traditionally involved the use of a retrovirus to insert a new gene into a random position on a chromosome. But by attaching zinc fingers (which determine where transcription factors bind) to endonucleases (which break DNA strands), homologous recombination
can be induced to correct and replace defective (or undesired) DNA
sequences. The first applications of this technology are to isolate stem cells from the bone marrow of patients having blood disease mutations, to correct those mutations in laboratory dishes using zinc finger endonucleases and to transplant the stem cells back into the patients.
Enhanced DNA repair has been proposed as a potential rejuvenation strategy.
Yet another option involves cosmetic changes to the individual to
create the appearance of youth. These are generally superficial and do
little to make the person healthier or live longer, but the real
improvement in a person's appearance may elevate their mood and have
positive side effects normally correlated with happiness. Cosmetic surgery
is a large industry offering treatments such as removal of wrinkles
("face lift"), removal of extra fat (liposuction) and reshaping or
augmentation of various body parts (abdomen, breasts, face).
There are also, as commonly found throughout history, many fake
rejuvenation products that have been shown to be ineffective. Chief
among these are powders, sprays, gels, and homeopathic
substances that claim to contain growth hormones. Authentic growth
hormones are only effective when injected, mainly due to the fact that
the 191-amino acid protein is too large to be absorbed through the mucous membranes, and would be broken up in the stomach if swallowed.
The Mprize
scientific competition is under way to deliver on the mission of
extending healthy human life. It directly accelerates the development of
revolutionary new life extension therapies by awarding two cash prizes:
one to the research team that breaks the world record for the
oldest-ever mouse; and one to the team that develops the most successful
late-onset rejuvenation. Current Mprize
winner for rejuvenation is Steven Spindler. Caloric restriction (CR),
the consumption of fewer calories while avoiding malnutrition, was
applied as a robust method of decelerating aging and the development of
age-related diseases.
The biomedical gerontologistAubrey de Grey
has initiated a project, strategies for engineered negligible
senescence (SENS), to study how to reverse the damage caused by aging.
He has proposed seven strategies for what he calls the seven deadly sins
of aging:
Senescent cells can be removed by activating the immune system against them. Or they can be destroyed by gene therapy to introduce "suicide genes" that only kill senescent cells.
Proteincross-linking can largely be reversed by drugs that break the links. But to break some of the cross-links we may need to develop enzymatic methods.
For intracellular junk we need to introduce new enzymes, possibly enzymes from soil bacteria, that can degrade the junk (lipofuscin) that our own natural enzymes cannot degrade.
For mitochondrial
mutations the plan is not to repair them but to prevent harm from the
mutations by putting suitably modified copies of the mitochondrial genes
into the cell nucleus by gene therapy. The mitochondrial DNA experiences a high degree of mutagenic damage because most free radicals are generated in the mitochondria. A copy of the mitochondrial DNA located in the nucleus will be better protected from free radicals, and there will be better DNA repair when damage occurs. All mitochondrial proteins would then be imported into the mitochondria.
For cancer (the most lethal consequence of mutations) the strategy is to use gene therapy to delete the genes for telomerase
and to eliminate telomerase-independent mechanisms of turning normal
cells into "immortal" cancer cells. To compensate for the loss of
telomerase in stem cells we would introduce new stem cells every decade or so.
In 2009, Aubrey de Grey co-founded the SENS Foundation to expedite progress in the above-listed areas.
Age-related memory loss, sometimes described as "normal aging" (also spelled "ageing" in British English), is qualitatively different from memory loss associated with types of dementia such as Alzheimer's disease, and is believed to have a different brain mechanism.
Mild cognitive impairment (MCI) is a condition in which people face
memory problems more often than that of the average person their age.
These symptoms, however, do not prevent them from carrying out normal
activities and are not as severe as the symptoms for Alzheimer's disease
(AD). Symptoms often include misplacing items, forgetting events or
appointments, and having trouble finding words.
According to recent research, MCI is seen as the transitional
state between cognitive changes of normal aging and Alzheimer's disease.
Several studies have indicated that individuals with MCI are at an
increased risk for developing AD, ranging from one percent to
twenty-five percent per year; in one study twenty-four percent of MCI
patients progressed to AD in two years and twenty percent more over
three years, whereas another study indicated that the progression of MCI
subjects was fifty-five percent in four and a half years. Some patients with MCI, however, never progress to AD.
Studies have also indicated patterns that are found in both MCI
and AD. Much like patients with Alzheimer's disease, those suffering
from mild cognitive impairment have difficulty accurately defining words
and using them appropriately in sentences when asked. While MCI
patients had a lower performance in this task than the control group, AD
patients performed worse overall. The abilities of MCI patients stood
out, however, due to the ability to provide examples to make up for
their difficulties. AD patients failed to use any compensatory
strategies and therefore exhibited the difference in use of episodic
memory and executive functioning.
Normal aging
Normal
aging is associated with a decline in various memory abilities in many
cognitive tasks; the phenomenon is known as age-related memory
impairment (AMI) or age-associated memory impairment (AAMI). The ability
to encode new memories of events or facts and working memory shows decline in both cross-sectional and longitudinal studies. Studies comparing the effects of aging on episodic memory, semantic memory, short-term memory and priming find that episodic memory is especially impaired in normal aging; some types of short-term memory are also impaired. The deficits may be related to impairments seen in the ability to refresh recently processed information.
Source information is one type of episodic memory that suffers
with old age; this kind of knowledge includes where and when the person
learned the information. Knowing the source and context of information
can be extremely important in daily decision-making, so this is one way
in which memory decline can affect the lives of the elderly. Therefore,
reliance on political stereotypes is one way to use their knowledge
about the sources when making judgments, and the use of metacognitive
knowledge gains importance.
This deficit may be related to declines in the ability to bind
information together in memory during encoding and retrieve those
associations at a later time.
Throughout the many years of studying the progression of aging
and memory, it has been hard to distinguish an exact link between the
two. Many studies have tested psychologists theories throughout the
years and they have found solid evidence that supports older adults
having a harder time recalling contextual information while the more
familiar or automatic information typically stays well preserved
throughout the aging process (Light, 2000). Also, there is an increase
of irrelevant information as one ages which can lead to an elderly
person believing false information since they are often in a state of
confusion.
Episodic memory is supported by networks spanning frontal,
temporal, and parietal lobes. The interconnections in the lobes are
presumed to enable distinct aspects of memory, whereas the effects of
gray matter lesions have been extensively studied, less is known about
the interconnecting fiber tracts. In aging, degradation of white matter
structure has emerged as an important general factor, further focusing
attention on the critical white matter connections.
Exercise affects many people young and old.
For the young, if exercise is introduced it can form a constructive
habit that can be instilled throughout adulthood. For the elderly,
especially those with Alzheimer's or other diseases that affect the
memory, when the brain is introduced to exercise the hippocampus is
likely to retain its size and improve its memory.
It is also possible that the years of education a person has had
and the amount of attention they received as a child might be a variable
closely related to the links of aging and memory.
There is a positive correlation between early life education and memory
gains in older age. This effect is especially significant in women.
In particular, associative learning,
which is another type of episodic memory, is vulnerable to the effects
of aging, and this has been demonstrated across various study paradigms.
This has been explained by the Associative Deficit Hypothesis (ADH),
which states that aging is associated with a deficiency in creating and
retrieving links between single units of information. This can include
knowledge about context, events or items. The ability to bind pieces of
information together with their episodic context in a coherent whole has
been reduced in the elderly population.
Furthermore, the older adults' performances in free recall involved
temporal contiguity to a lesser extent than for younger people,
indicating that associations regarding contiguity become weaker with
age.
Several reasons have been speculated as to why older adults use
less effective encoding and retrieval strategies as they age. The first
is the "disuse" view, which states that memory strategies are used less
by older adults as they move further away from the educational system.
Second is the "diminished attentional capacity" hypothesis, which means
that older people engage less in self-initiated encoding due to reduced
attentional capacity. The third reason is the "memory self-efficacy,"
which indicates that older people do not have confidence in their own
memory performances, leading to poor consequences.
It is known that patients with Alzheimer's disease and patients with
semantic dementia both exhibit difficulty in tasks that involve picture
naming and category fluency. This is tied to damage to their semantic network, which stores knowledge of meanings and understandings.
One phenomenon, known as "Senior Moments", is a memory deficit
that appears to have a biological cause. When an older adult is
interrupted while completing a task, it is likely that the original task
at hand can be forgotten. Studies have shown that the brain of an
older adult does not have the ability to re-engage after an interruption
and continues to focus on the particular interruption unlike that of a
younger brain.
This inability to multi-task is normal with aging and is expected to
become more apparent with the increase of older generations remaining in
the work field.
A biological explanation for memory deficits in aging includes a
postmortem examination of five brains of elderly people with better
memory than average. These people are called the "super aged," and it
was found that these individuals had fewer fiber-like tangles of tau
protein than in typical elderly brains. However, a similar amount of
amyloid plaque was found.
More recent research has extended established findings of age related decline in executive functioning,
by examining related cognitive processes that underlie healthy older
adults' sequential performance. Sequential performance refers to the
execution of a series steps needed to complete a routine, such as the
steps required to make a cup of coffee or drive a car. An important part
of healthy aging involves older adults' use of memory and inhibitory
processes to carry out daily activities in a fixed order without
forgetting the sequence of steps that were just completed while
remembering the next step in the sequence. A study from 2009
examined how young and older adults differ in the underlying
representation of a sequence of tasks and their efficiency at retrieving
the information needed to complete their routine. Findings from this
study revealed that when older and young adults had to remember a
sequence of eight animal images arranged in a fixed order, both age
groups spontaneously used the organizational strategy of chunking to
facilitate retrieval of information. However, older adults were slower
at accessing each chunk compared to younger adults, and were better able
to benefit from the use of memory aids, such as verbal rehearsal to
remember the order of the fixed sequence. Results from this study
suggest that there are age differences in memory and inhibitory
processes that affect people's sequence of actions and the use of memory
aids could facilitate the retrieval of information in older age.
Causes
The
causes for memory issues and aging is still unclear, even after the many
theories have been tested. There has yet to be a distinct link between
the two because it is hard to determine exactly how each aspect of aging
effects the memory and aging process. However, it is known that the
brain shrinks with age due to the expansion of ventricles
causing there to be little room in the head. Unfortunately, it is hard
to provide a solid link between the shrinking brain and memory loss due
to not knowing exactly which area of the brain has shrunk and what the
importance of that area truly is in the aging process (Baddeley,
Anderson, & Eysenck, 2015)
Attempting to recall information or a situation that has happened can be
very difficult since different pieces of information of an event are
stored in different areas. During recall of an event, the various pieces
of information are pieced back together again and any missing
information is filled up by our brains, unconsciously which can account
for ourselves receiving and believing false information (Swaab, 2014).
Some memory issues are due to stress, anxiety, or depression. A traumatic life event, such as the death of a spouse,
can lead to changes in lifestyle and can leave an elderly person
feeling unsure of themselves, sad, and lonely. Dealing with such drastic
life changes can therefore leave some people confused or forgetful.
While in some cases these feelings may fade, it is important to take
these emotional problems seriously. By emotionally supporting a struggling relative and seeking help from a doctor or counselor, the forgetfulness can be improved.
Memory loss can come from different situations of trauma
including accidents, head-injuries and even from situations of abuse in
the past. Sometimes the memories of traumas can last a lifetime and
other times they can be forgotten, intentionally or not, and the causes
are highly debated throughout psychology. There is a possibility that
the damage to the brain makes it harder for a person to encode and
process information that should be stored in long-term memory
(Nairne, 2000). There is support for environmental cues being helpful
in recovery and retrieval of information, meaning that there is enough
significance to the cue that it brings back the memory.
Theories
Tests and data show that as people age, the contiguity effect, which is stimuli that occur close together in the associated time, starts to weaken.
This is supported by the associative deficit theory of memory, which
access the memory performance of an elder person and is attributed to
their difficulty in creating and retaining cohesive episodes. The
supporting research in this test, after controlling for sex, education,
and other health-related issues, show that greater age was associated
with lower hit and greater false alarm rates, and also a more liberal
bias response on recognition tests.
Older people have a higher tendency to make outside intrusions
during a memory test. This can be attributed to the inhibition effect.
Inhibition caused participants to take longer time in recalling or
recognizing an item, and also subjected the participants to make more
frequent errors. For instance, in a study using metaphors as the test
subject, older participants rejected correct metaphors more often than
literally false statements.
Working memory, which as previously stated is a memory system
that stores and manipulates information as we complete cognitive tasks,
demonstrates great declines during the aging process. There have been
various theories offered to explain why these changes may occur, which
include fewer attentional resources, slower speed of processing, less
capacity to hold information, and lack of inhibitory control. All of
these theories offer strong arguments, and it is likely that the decline
in working memory is due to the problems cited in all of these areas.
Some theorists argue that the capacity of working memory decreases as we age, and we are able to hold less information.
In this theory, declines in working memory are described as the result
of limiting the amount of information an individual can simultaneously
keep active, so that a higher degree of integration and manipulation of
information is not possible because the products of earlier memory
processing are forgotten before the subsequent products.
Another theory that is being examined to explain age related
declines in working memory is that there is a limit in attentional
resources seen as we age. This means that older individuals are less
capable of dividing their attention between two tasks, and thus tasks
with higher attentional demands are more difficult to complete due to a
reduction in mental energy.
Tasks that are simple and more automatic, however, see fewer declines
as we age. Working memory tasks often involve divided attention, thus
they are more likely to strain the limited resources of aging
individuals.
Speed of processing is another theory that has been raised to
explain working memory deficits. As a result of various studies he has
completed examining this topic, Salthouse argues that as we age our
speed of processing information decreases significantly. It is this
decrease in processing speed that is then responsible for our inability
to use working memory efficiently as we age.
The younger persons brain is able to obtain and process information at a
quicker rate which allows for subsequent integration and manipulation
needed to complete the cognitive task at hand. As this processing slows,
cognitive tasks that rely on quick processing speed then become more
difficult.
Finally, the theory of inhibitory control has been offered to
account for decline seen in working memory. This theory examines the
idea that older adults are unable to suppress irrelevant information in
working memory, and thus the capacity for relevant information is
subsequently limited. Less space for new stimuli due may attribute to
the declines seen in an individual's working memory as they age.
As we age, deficits are seen in the ability to integrate,
manipulate, and reorganize the contents of working memory in order to
complete higher level cognitive tasks such as problem solving, decision
making, goal setting, and planning. More research must be completed in
order to determine what the exact cause of these age-related deficits in
working memory are. It is likely that attention, processing speed,
capacity reduction, and inhibitory control may all play a role in these
age-related deficits. The brain regions that are active during working
memory tasks are also being evaluated, and research has shown that
different parts of the brain are activated during working memory in
younger adults as compared to older adults. This suggests that younger
and older adults are performing these tasks differently.
Types of studies
There are two different methods for studying the ways aging and memory effect each other which are cross-sectional and longitudinal.
Both methods have been used multiple times in the past, but they both
have advantages and disadvantages. Cross-sectional studies include
testing different groups of people at different ages on a single
occasion. This is where most of the evidence for studies including
memory and aging come from. The disadvantage of cross-sectional studies
is not being able to compare current data to previous data, or make a
prediction about the future data. Longitudinal studies include testing
the same group of participants the same number of times, over many years
which are carefully selected in order to reflect upon a full range of a
population (Ronnlund, Nyberg, Backman, & Nilsson; Ronnlund &
Nilsson, 2006). The advantage to longitudinal studies include being able
to see the effects that aging has on performance for each participant
and even being able to distinguish early signs of memory related
diseases. However, this type of study can be very costly and timely
which might make it more likely to have participants drop out over the
course of the study. (Baddeley, Anderson, & Eysenck, 2015).
In 2010, experiments that have tested for the significance of
under-performance of memory for an older adult group as compared to a
young adult group, hypothesized that the deficit in associate memory due
to age can be linked with a physical deficit. This deficit can be
explained by the inefficient processing in the medial-temporal regions.
This region is important in episodic memory, which is one of the two
types of long-term human memory, and it contains the hippocampi, which
are crucial in creating memorial association between items.
Age-related memory loss is believed to originate in the dentate gyrus, whereas Alzheimer's is believed to originate in the entorhinal cortex.
During normal aging, oxidative DNA damage in the brain accumulates in the promoters of genes involved in learning and memory, as well as in genes involved in neuronal survival. Oxidative DNA damage includes DNA single-strand breaks which can give rise to DNA double-strand breaks (DSBs). DSBs accumulate in neurons and astrocytes of the hippocampus and frontal cortex at early stages and during the progression to Alzheimer’s disease, a process that could be an important driver of neurodegeneration and cognitive decline.
Prevention and treatment
Various actions have been suggested to prevent memory loss or even improve memory.
The Mayo Clinic has suggested seven steps: stay mentally active, socialize regularly, get organized, eat a healthy diet, include physical activity in your daily routine, and manage chronic conditions. Because some of the causes of memory loss include medications, stress, depression, heart disease,
excessive alcohol use, thyroid problems, vitamin B12 deficiency, not
drinking enough water, and not eating nutritiously, fixing those
problems could be a simple, effective way to slow down dementia.
Some say that exercise is the best way to prevent memory problems,
because that would increase blood flow to the brain and perhaps help new
brain cells grow.
The treatment will depend on the cause of memory loss, but
various drugs to treat Alzheimer's disease have been suggested in recent
years. There are four drugs currently approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's, and they all act on the cholinergic system: Donepezil, Galantamine, Rivastigmine, and Tacrine.
Although these medications are not the cure for Alzheimer's, symptoms
may be reduced for up to eighteen months for mild or moderate dementia.
These drugs do not forestall the ultimate decline to full Alzheimer's.
Also, modality is important in determining the strength of the
memory. For instance, auditory creates stronger memory abilities than
visual. This is shown by the higher recency and primacy effects of an
auditory recall test compared to that of a visual test. Research has
shown that auditory training, through instrumental musical activity
or practice, can help preserve memory abilities as one ages.
Specifically, in Hanna-Pladdy and McKay's experiment, they tested and
found that the number of years of musical training, all things equal,
leads to a better performance in non-verbal memory and increases the
life span on cognition abilities in one's advanced years.
Caregiving
By
keeping the patient active, focusing on their positive abilities, and
avoiding stress, these tasks can easily be accomplished. Routines for
bathing and dressing must be organized in a way so that the individual
still feels a sense of independence. Simple approaches such as finding
clothes with large buttons, elastic waist bands, or Velcro straps can
ease the struggles of getting dressed in the morning. Further, finances
should be managed or have a trusted individual appointed to manage
them. Changing passwords to prevent over-use and involving a trusted
family member or friend in managing accounts can prevent financial
issues. When household chores begin to pile up, find ways to break down
large tasks into small, manageable steps that can be rewarded.
Finally, talking with and visiting a family member or friend with memory
issues is very important. Using a respectful and simple approach,
talking one-on-one can ease the pain of social isolation and bring much
mental stimulation.
Many people who experience memory loss and other cognitive impairments
can have changes in behaviors that are challenging to deal with for care
givers. See also Caregiver stress.
To help caregivers should learn different ways to communicate and to
deescalate possibly aggressive situations. Because decision making
skills can be impaired, it can be beneficial to give simple commands
instead of asking multiple questions. See also Caring for People with Dementia.
Caregiving can be a physically, mentally, and emotionally taxing job to
take on. A caregiver also needs to remember to care for themselves,
taking breaks, finding time to themselves and possibly joining a support
group are a few ways to avoid burnout.
Domains of memory spared vs. affected
In contrast, implicit, or procedural memory, typically shows no decline with age. Other types of short-term memory show little decline, and semantic knowledge (e.g. vocabulary) actually improves with age. In addition, the enhancement seen in memory for emotional events is also maintained with age.
Losing working memory has been cited as being the primary reason
for a decline in a variety of cognitive tasks due to aging. These tasks
include long-term memory, problem solving, decision making, and
language.
Working memory involves the manipulation of information that is being
obtained, and then using this information to complete a task. For
example, the ability of one to recite numbers they have just been given
backwards requires working memory, rather than just simple rehearsal of
the numbers which would require only short-term memory. One's ability to
tap into one's working memory declines as the aging process progresses.
It has been seen that the more complex a task is, the more difficulty
the aging person has with completing this task. Active reorganization
and manipulation of information becomes increasingly harder as adults
age.
When an older individual is completing a task, such as having a
conversation or doing work, they are using their working memory to help
them complete this task. As they age, their ability to multi-task seems
to decline; thus after an interruption it is often more difficult for an
aging individual to successfully finish the task at hand.
Additionally, working memory plays a role in the comprehension and
production of speech. There is often a decline in sentence comprehension
and sentence production as individuals age. Rather than linking this
decline directly to deficits in linguistic ability, it is actually
deficits in working memory that contribute to these decreasing language
skills.
Qualitative changes
Most
research on memory and aging has focused on how older adults perform
worse at a particular memory task. However, researchers have also
discovered that simply saying that older adults are doing the same
thing, only less of it, is not always accurate. In some cases, older
adults seem to be using different strategies than younger adults. For
example, brain imaging studies have revealed that older adults are more
likely to use both hemispheres when completing memory tasks than younger
adults. In addition, older adults sometimes show a positivity effect when remembering information, which seems to be a result of the increased focus on regulating emotion seen with age. For instance, eye tracking reveals that older adults showed preferential looking toward happy faces and away from sad faces.
Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use with the start of the journal BIOGERONTOLOGY in 2000. It involves interdisciplinary research on the causes, effects, and mechanisms of biological aging. Biogerontologist Leonard Hayflick
has said that the natural average lifespan for a human is around 92
years and, if humans do not invent new approaches to treat aging, they
will be stuck with this lifespan. James Vaupel has predicted that life expectancy in industrialized countries will reach 100 for children born after the year 2000.
Many surveyed biogerontologists have predicted life expectancies of
more than three centuries for people born after the year 2100.
Other scientists, more controversially, suggest the possibility of
unlimited lifespans for those currently living. For example, Aubrey de Grey offers the "tentative timeframe" that with adequate funding of research to develop interventions in aging such as strategies for engineered negligible senescence,
"we have a 50/50 chance of developing technology within about 25 to 30
years from now that will, under reasonable assumptions about the rate of
subsequent improvements in that technology, allow us to stop people
from dying of aging at any age".
The idea of this approach is to use presently available technology to
extend lifespans of currently living humans long enough for future
technological progress to resolve any remaining aging-related issues.
This concept has been referred to as longevity escape velocity.
Biomedical gerontology,
also known as experimental gerontology and life extension, is a
sub-discipline of biogerontology endeavoring to slow, prevent, and even
reverse aging in both humans and animals.
Approaches to aging
Wrinkled skin on the face is a characteristic feature of old people
Biogerontologists vary in the degree to which they focus on the study of the aging process as a means of mitigating the diseases of aging,
or as a method for extending lifespan. A relatively new
interdisciplinary field called geroscience focuses on preventing
diseases of aging and prolonging the 'healthspan' over which an
individual lives without serious illness. The approach of biogerontologists is that aging is diseaseper se
and should be treated directly, with the ultimate goal of having the
probability of individual dying be independent of their age (if external
factors are held constant). This is in contrast to the opinion that maximum life span can not, or should not, be altered.
Biogerontology should not be confused with geriatrics,
which is a field of medicine that studying the treatment of existing
disease in aging people, rather than the treatment of aging itself.
There are numerous theories of aging, and no one theory has been
entirely accepted. At their extremes, the wide spectrum of aging
theories can be categorized into programmed theories - which imply that
aging follows a biological timetable, and error theories - which suggest
aging occurs due to cumulative damage experienced by organisms.
Stochastic theories
Stochastic
theories of aging are theories suggesting that aging is caused by small
changes in the body over time and the body's failure to restore the
system and mend the damages to the body. Cells and tissues are injured
due to the accumulation of damage over time resulting in the diminished
functioning of organs. The notion of accumulated damage was first
introduced in 1882 by biologist Dr. August Weismann as the "wear and tear" theory.
Wear and tear theories
Wear and tear theories of aging began to be introduced yet in 19th century.
They suggest that as an individual ages, body parts such as cells and
organs wear out from continued use. Wearing of the body can be
attributable to internal or external causes that eventually lead to an
accumulation of insults
which surpasses the capacity for repair. Due to these internal and
external insults, cells lose their ability to regenerate, which
ultimately leads to mechanical and chemical exhaustion. Some insults
include chemicals in the air, food, or smoke. Other insults may be
things such as viruses, trauma, free radicals, cross-linking, and high body temperature.
Accumulation
Accumulation
theories of aging suggest that aging is bodily decline that results
from an accumulation of elements, whether introduced to the body from
the environment or resulting from cell metabolism.
Mutation accumulation theory was first proposed by Peter Medawar in 1952 as an evolutionary explanation for biological ageing and the associated decline in fitness that accompanies it. The theory explains that, in the case where harmful mutations
are only expressed later in life, when reproduction has ceased and
future survival is increasingly unlikely, then these mutations are
likely to be unknowingly passed on to future generations. In this situation the force of natural selection
will be weak, and so insufficient to consistently eliminate these
mutations. Medawar posited that over time these mutations would
accumulate due to genetic drift and lead to the evolution of what is now referred to as ageing.
Free radicals are reactive molecules produced by cellular and environmental processes, and can damage the elements of the cell such as the cell membrane and DNA
and cause irreversible damage. The free-radical theory of aging
proposes that this damage cumulatively degrades the biological function
of cells and impacts the process of aging. The idea that free radicals are toxic agents was first proposed by Rebeca Gerschman and colleagues in 1945, but came to prominence in 1956, when Denham Harman
proposed the free-radical theory of aging and even demonstrated that
free radical reactions contribute to the degradation of biological
systems. Oxidative damage of many types accumulate with age, such as oxidative stress that oxygen-free radicals, because the free radical theory of aging argues that aging results from the damage generated by reactive oxygen species (ROS).
ROS are small, highly reactive, oxygen-containing molecules that can
damage a complex of cellular components such as fat, proteins, or from
DNA; they are naturally generated in small amounts during the body's
metabolic reactions. These conditions become more common as humans grow
older and include diseases related to aging, such as dementia, cancer
and heart disease. Amount of free radicals in the cell can be reduced
with help of antioxidants.
But there's a problem that some free radicals are used by organism as
signal molecules, and too active general reduction of free radicals
causes to organism more harm than good. Some time ago idea of slowing
aging using antioxidants were very popular but now high doses of
antioxidants are considered harmful. At present some scientists try to
invent approaches of local suppression of free radicals only in certain
places of cells. Efficiency of such approach remains to be unclear, research is ongoing.
DNA damage has been one of the major causes in diseases related to aging. The stability of the genome
is defined by the cells machinery of repair, damage tolerance, and
checkpoint pathways that counteracts DNA damage. One hypothesis proposed
by physicist Gioacchino Failla in 1958 is that damage accumulation to the DNA causes aging. The hypothesis was developed soon by physicist Leó Szilárd.
This theory has changed over the years as new research has discovered
new types of DNA damage and mutations, and several theories of aging
argue that DNA damage with or without mutations causes aging.
DNA damage is distinctly different from mutation, although both are types of error in DNA.
DNA damage is an abnormal chemical structure in DNA, while a mutation
is a change in the sequence of standard base pairs. The theory that DNA
damage is the primary cause of aging is based, in part, on evidence in
human and mouse that inherited deficiencies in DNA repair genes often
cause accelerated aging.
There is also substantial evidence that DNA damage accumulates with age
in mammalian tissues, such as those of the brain, muscle, liver and
kidney (see DNA damage theory of aging and DNA damage (naturally occurring)).
One expectation of the theory (that DNA damage is the primary cause of
aging) is that among species with differing maximum life spans, the
capacity to repair DNA damage should correlate with lifespan. The first
experimental test of this idea was by Hart and Setlow
who measured the capacity of cells from seven different mammalian
species to carry out DNA repair. They found that nucleotide excision
repair capability increased systematically with species longevity. This
correlation was striking and stimulated a series of 11 additional
experiments in different laboratories over succeeding years on the
relationship of nucleotide excision repair and life span in mammalian
species (reviewed by Bernstein and Bernstein).
In general, the findings of these studies indicated a good correlation
between nucleotide excision repair capacity and life span. Further
support for the theory that DNA damage is the primary cause of aging
comes from study of Poly ADP ribose polymerases
(PARPs). PARPs are enzymes that are activated by DNA strand breaks and
play a role in DNA base excision repair. Burkle et al. reviewed
evidence that PARPs, and especially PARP-1, are involved in maintaining
mammalian longevity.
The life span of 13 mammalian species correlated with poly(ADP
ribosyl)ation capability measured in mononuclear cells. Furthermore,
lymphoblastoid cell lines from peripheral blood lymphocytes of humans
over age 100 had a significantly higher poly(ADP-ribosyl)ation
capability than control cell lines from younger individuals.
Cross-linking theory
The cross-linking theory proposes that advanced glycation end-products (stable bonds formed by the binding of glucose to proteins) and other aberrant cross-links
accumulating in aging tissues is the cause of aging. The crosslinking
of proteins disables their biological functions. The hardening of the connective tissue, kidney diseases, and enlargement of the heart are connected to the cross-linking of proteins. Crosslinking of DNA can induce replication errors, and this leads to deformed cells and increases the risk of cancer.
Genetic
Genetic
theories of aging propose that aging is programmed within each
individual's genes. According to this theory, genes dictate cellular
longevity. Programmed cell death, or apoptosis,
is determined by a "biological clock" via genetic information in the
nucleus of the cell. Genes responsible for apoptosis provide an
explanation for cell death, but are less applicable to death of an
entire organism. An increase in cellular apoptosis may correlate to
aging, but is not a 'cause of death'. Environmental factors and genetic
mutations can influence gene expression and accelerate aging.
More recently epigenetics have been explored as a contributing factor. The epigenetic clock,
which relatively objectively measures the biological age of cells, are
useful tool for testing different anti-aging approaches. The most famous epigenetic clock is Horvath's clock, but now already more accurate analogues have appeared.
General imbalance
General imbalance theories of aging suggest that body systems, such as the endocrine, nervous, and immune systems, gradually decline and ultimately fail to function. The rate of failure varies system by system.
Immunological theory
The
immunological theory of aging suggests that the immune system weakens
as an organism ages. This makes the organism unable to fight infections
and less able to destroy old and neoplastic cells. This leads to aging and will eventually lead to death. This theory of aging was developed by Roy Walford in 1969. According to Walford, incorrect immunological procedures are the cause of the process of aging.
DNA repair defects are seen in nearly all of the diseases described as accelerated aging disease, in which various tissues, organs or systems of the human body age prematurely. Because the accelerated aging diseases display different aspects of aging, but never every aspect, they are often called segmental progerias by biogerontologists.
deletion of ATR in adult mice leads to a number of disorders
including hair loss and graying, kyphosis, osteoporosis, premature
involution of the thymus, fibrosis of the heart and kidney and decreased
spermatogenesis
deficient transcription coupled NER with time-dependent accumulation of transcription-blocking damages; mouse life span reduced from 2.5 years to 5 months;) Ercc1−/−
mice are leukopenic and thrombocytopenic, and there is extensive
adipose transformation of the bone marrow, hallmark features of normal
aging in mice
some mutations in ERCC2 cause Cockayne syndrome
in which patients have segmental progeria with reduced stature, mental
retardation, cachexia (loss of subcutaneous fat tissue), sensorineural
deafness, retinal degeneration, and calcification of the central nervous
system; other mutations in ERCC2 cause trichothiodystrophy
in which patients have segmental progeria with brittle hair, short
stature, progressive cognitive impairment and abnormal face shape; still
other mutations in ERCC2 cause xeroderma pigmentosum (without a progeroid syndrome) and with extreme sun-mediated skin cancer predisposition
mutations in ERCC4 cause symptoms of accelerated aging that affect
the neurologic, hepatobiliary, musculoskeletal, and hematopoietic
systems, and cause an old, wizened appearance, loss of subcutaneous fat,
liver dysfunction, vision and hearing loss, chronic kidney disease, muscle wasting, osteopenia, kyphosis and cerebral atrophy
mice with deficient ERCC5 show loss of subcutaneous fat, kyphosis,
osteoporosis, retinal photoreceptor loss, liver aging, extensive
neurodegeneration, and a short lifespan of 4–5 months
premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines
premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines
deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein with retarded repair of 6-4-photoproducts
SIRT6-deficient mice develop profound lymphopenia, loss of
subcutaneous fat and lordokyphosis, and these defects overlap with
aging-associated degenerative processes
mice defective in SIRT7 show phenotypic and molecular signs of
accelerated aging such as premature pronounced curvature of the spine,
reduced life span, and reduced non-homologous end joining
lack of Zmpste24 prevents lamin A formation and causes progeroid
phenotypes in mice and humans, increased DNA damage and chromosome
aberrations, sensitivity to DNA-damaging agents and deficiency in
homologous recombination
DNA repair defects distinguished from "accelerated aging"
Most of the DNA repair deficiency diseases show varying degrees of "accelerated aging" or cancer (often some of both). But elimination of any gene essential for base excision repair kills the embryo—it is too lethal to display symptoms (much less symptoms of cancer or "accelerated aging").
Rothmund-Thomson syndrome and xeroderma pigmentosum display symptoms
dominated by vulnerability to cancer, whereas progeria and Werner
syndrome show the most features of "accelerated aging". Hereditary nonpolyposis colorectal cancer (HNPCC) is very often caused by a defective MSH2 gene leading to defective mismatch repair, but displays no symptoms of "accelerated aging".
On the other hand, Cockayne Syndrome and trichothiodystrophy show
mainly features of accelerated aging, but apparently without an
increased risk of cancer. Some DNA repair defects manifest as neurodegeneration rather than as cancer or "accelerated aging". (Also see the "DNA damage theory of aging" for a discussion of the evidence that DNA damage is the primary underlying cause of aging.)
Debate concerning "accelerated aging"
Some
biogerontologists question that such a thing as "accelerated aging"
actually exists, at least partly on the grounds that all of the
so-called accelerated aging diseases are segmental progerias. Many
disease conditions such as diabetes, high blood pressure, etc., are associated with increased mortality. Without reliable biomarkers of aging it is hard to support the claim that a disease condition represents more than accelerated mortality.
Against this position other biogerontologists argue that premature aging phenotypes are identifiable symptoms associated with mechanisms of molecular damage. The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging". Such conditions, it is argued, are readily distinguishable from genetic diseases associated with increased mortality, but not associated with an aging phenotype, such as cystic fibrosis and sickle cell anemia.
It is further argued that segmental aging phenotype is a natural part
of aging insofar as genetic variation leads to some people being more
disposed than others to aging-associated diseases such as cancer and Alzheimer's disease.
DNA repair defects and increased cancer risk
Individuals with an inherited impairment in DNA repair capability are often at increased risk of cancer. When a mutation
is present in a DNA repair gene, the repair gene will either not be
expressed or be expressed in an altered form. Then the repair function
will likely be deficient, and, as a consequence, damages will tend to
accumulate. Such DNA damages can cause errors during DNA synthesis
leading to mutations, some of which may give rise to cancer. Germ-line
DNA repair mutations that increase the risk of cancer are listed in the
Table.
