As a neurologist specializing in brain aging I am often asked about our prospects for a long life of healthy aging, free of mental decline. Most moving are those who want to know how to keep their brain fit in the face of caring for a loved one suffering with Alzheimer’s disease. Especially among those touched by Alzheimer’s disease there seems to be almost a pervasive fear that if they live long enough their fate too will be dementia. I know that because of what I do, I tend to attract such questions about dementia, not unlike I imagine a knowledgeable cook is consulted by us kitchen novices for remedies to a world seemingly filled with collapsed cakes and congealed sauces. Of course not all are worried either about their brains (or their baking). There are certainly older people who remain the proverbial “sharp as a tack,” clear thinkers into the ninth or tenth decade of life. Thus we do seem to be literally of two minds about our aging health.

On the one hand there are images of individuals at advanced ages actively engaged as if they were Gen-Xers who never change. These are the familiar pictures one sees advertising the good life in a golden retirement. On the other hand, are the frightening images of thousands of elderly with limited capacities, confined to a nursing home or some other sheltered living situation. Which of these is closer to the truth? As with most stark contrasts, there is truth in both. The vision of an army of active seniors is not that far from the truth. In fact, most individuals who are in their 60s or 70s remain quite independent and active and, if financially secure, can enjoy good health and a reasonable quality of life. However, if we consider where our aging population will be in the next 20 to 50 years, there is a somewhat different picture. This future society will be radically changed by the demographics of aging. Specifically, it is in this next 50 years that we will see unprecedented growth in the number of elderly over age 85. Moreover, we will see an eleven-fold increase in the number of projected centenarians in the next 50 years. Assuming life expectancy trends continue to increase in the United States, we will go from our current centenarian population of less than 100,000 to over 800,000 centenarians by the year 2050. There is no reason not to expect these numbers to grow; life expectancy has unremittingly increased each year since 1900.

The roots of this remarkable demographic change began only recently, at the beginning of this past century. If you were born in 1900, your life expectancy at birth would have been on average only 49 years. Moving back even further in time, one realizes that as a species our life expectancy at birth was perhaps only 20 to 30 years even as recently as the middle ages. Thus, we have seen a remarkable increase in the number of people reaching advanced ages. This spectacular increase in longevity might be considered one of our supreme achievements as a species, except for the accompanying problem of loss of the ability to remain independent at current oldest ages. Among those individuals who reach the age of 75, only about 10-15 percent will require any assistance for activities of daily living. However, those who are 85 and older require four to five times more assistance with everyday activities. As one moves even further up in age, it becomes more the exception than the rule to find truly independently living elders. Thus, it is extremely rare to find centenarians who are truly independent and functioning on their own. A recent complete population study of three Dutch cities identified all 17 centenarians among 250,000 individuals in these metropolitan areas. All but two were demented (and even the two seemingly independent persons probably had at least mild cognitive impairment).

Does this mean that with increased longevity it is impossible to survive to 100 without preserved function? No, there are very rare individuals of advanced ages who have been able to preserve good function. In our study of exceptional aging in Oregon we have been searching for individuals who have become very old without any health or cognitive problems. These are the exceptionally healthy oldest old, a select group of people living independently in the community without hypertension, diabetes, heart disease, cancer, or dementia. They are very rare. We estimate that they are only about 1 percent of all people age 85 or older. During the past ten years we have been able to identify only 4 centenarians in the Portland, Oregon metropolitan area who met stringent criteria for cognitive health and functional independence. Nevertheless, although very rare, we do know that some can escape the force of decline in health and function with advanced age.

We know that exceptional health among centenarians is possible. What then ultimately determines one’s ability to live not only long, but in a state of functional health and independence? Realizing that the current longevity explosion is only about 100 years old, a first place to look critically is at the events of the past century. Clearly something changed radically in the last century to dramatically increase our longevity. It is unlikely that this change has been a genetic or inherited modification in our DNA or genetic makeup. Evolution just doesn’t work on that time scale. In our rather short evolutionary history as a species of maybe 100,000 years, we have only had time to make genetic changes that are rather minor such as superficial features of skin color or facial appearance. Thus, it is more likely that this longevity extension is the result of changes in our environment rather than in our genes. Despite the medicalization of health in this past century, any observed changes favorable to longevity were not likely to have been the result of major medical breakthroughs. More plausible environmental explanations for this growth in longevity, are innovations and incorporation of principles of public health, sanitation and life style (with some influence related to medical advances as well).

Despite realizing the marked impact that the past century’s environment must have had in increasing longevity, one cannot ignore the effect of genetics. It could be said that we didn’t know we had this aging capability until certain genes key to aging were expressed in the new longevity permissive environment of the past century. The seeds of this potential for long life were sown millions of years ago. We know that as a species we are among the longest living mammals even in the rough and wild world of previous millennia. We slowly developed to this position as a long-lived species after millions of years of evolution. Our closest living evolutionary relatives, the chimpanzees are also relatively long-lived (about 60 years from records collected at zoos), but obviously still differ by quite a few years in maximum life span. If one takes this evolutionary theory of aging potential to its logical conclusion, one realizes that the genes that have been so important for us as a species are not really aging genes per se. The key genes are those that evolved to ensure our successful ability to survive as a species, to reproduce and nurture our children so that they might pass those genes on to their children. Thus, strictly speaking there are no “aging genes,” only genes that after the active young adult periods of reproduction and child rearing become basically purposeless genes without much of a role to play. They are what I call “dumb luck” genes, genes that have essentially been left over from a previous era of short life expectancy that when put into our current environment have potential either to help or harm us when we arrive our current later years as octogenarians and beyond. This notion has been embodied by the concept of antagonistic pleiotropy, the theory that genes having multiple (pleiotropic) effects good for fitness of a species at younger ages become even detrimental at older ages. An example of this phenomenon may be found in the genes that regulate function of the sex hormones, testosterone and estrogen. Both are obviously crucial for reproductive fitness, but at later ages may stimulate tumor growth leading to death secondary to prostate or breast cancers. Encompassing this concept is perhaps a more benign version contained in sets of “dumb luck” genes that are along for the ride, remaining active after they’ve done their bit toward our species’ survival and now in our current environment not too detrimental to our health in the post-reproductive years. Of course if we find ourselves someday living routinely to age 200 then at least some of these genes may not be considered as “lucky” as others. Nevertheless, at least at this time if there are genes that don’t have a hand in our demise at earlier adult ages, but seem to be compatible with better survival at late ages, then these must be considered relatively fortuitous genes.

Aside from this evolutionary perspective on aging there is further contemporary evidence of a genetic link to successful longevity. Among the most striking are observations of human twin longevity. Identical or monozygotic twins, tend to inherit longevity more closely than non-identical or dizygotic twins. Other evidence that there are some strong genetic components to aging and longevity is found among other animals where single genes can be mutated or changed that result in longer lives in animals bred for longevity. One of the first of these was a gene found in the roundworm, Caenorhabdites elegans, called daf-2, that in mutated form results in a doubling of the normal life span in this tiny worm. In this case, the worm goes from living two weeks to four weeks. This kind of observation has generated an entire biological cottage industry in searching for longevity genes among various species. This search has led to the recognition of several genes affecting life-span across a wide spectrum of species from fruit flies to mice.

Whether there are similar genes in humans remains a discussion of intense debate among gerontologists. Perhaps the closest identification of such a gene has been the discovery of a mutation of a gene in individuals who develop a syndrome which has sometimes been referred to as a premature or accelerated aging syndrome called Werner’s syndrome. This is one of the progeria syndromes (meaning premature aging). In Werner’s syndrome, individuals appear normal until adolescence or early adulthood. However, they quickly develop the appearance of premature aging, including thinning of the hair, wrinkling of the skin and atrophy of the muscles. Aside from these outward aging-like manifestations, these unfortunate individuals also suffer from cataracts, diabetes, heart disease and cancers, which ultimately lead to their premature death usually in the fourth decade of life. Interestingly, the gene that has been identified as causing Werner’s syndrome is a protein called helicase that acts to unwind the DNA double helix presumably to aid in its normal repair. Of particular interest in this human syndrome of aging is the fact that the brain appears spared from aging changes. This has led to the concept of segmental aging, meaning that genetic controls on aging may well not affect the entire organism in a broad sense, but only isolated organs or physiological systems.

In light of the Werner syndrome segmental aging phenotype, or outward aging appearance produced by a single gene mutation, one might consider the possibility that there exist analogous genes closely associated with brain aging. This possibility is particularly important when one considers the major causes of chronic disability among the very elderly where there is a major impact of brain changes. The “big three can’ts” of chronic aging disability are: can’t perceive, can’t move, and can’t think. In the category of problems perceiving, the most devastating changes involve difficulties with the visual system and changes reflecting problems with hearing. Despite these kinds of sensory deficits creating a considerable amount of disability many affected individuals remain remarkably independent in the community. Similarly, difficulty with mobility is also a major cause of disability with aging often secondary to changes of the musculoskeletal system, but also associated with deficits encountered with changes in central nervous system control such as difficulty with balance and gait. Often these mobility deficits are the result of diseases associated with aging such as stroke or Parkinson’s disease. Nevertheless, like sensory deficits such as blindness or deafness, even major losses of mobility of any cause do not necessarily mean the end to independence.

The only unequivocal change associated with aging and resulting in an irrefutable loss of independent function is the loss of mental capacities associated with dementia. This problem which now affects about 4 million Americans, to my mind thus forms the most crucial and pressing challenge of achieving a long, but independent life. Considering that there is ample evidence for genetic mechanisms acting to influence longevity, this is a challenge that I think will be met in the coming century. Accordingly, it seems reasonable to propose that there is a set of segmentally acting genes for the brain - a suite of genes that result in successful brain aging that would have a profound effect on allowing us to remain independent even at very advanced ages. When these genes (and the environments that nurture them) are uncovered we will have gained entry to a deeper understanding of how to sustain a long life free of dementia.

What clues might we have today for finding these genes? To uncover these healthy brain aging genes one needs to return to the concept of genes and environments once again. In this case one would reframe the question to ask are there some relationships or actions specific or important to brain function that have historically led to our potential as a species to live longer than most. To further examine this question, one needs to consider more closely how we came to be such a long-lived species. Information comes from examining our evolutionary tree. We all evolved from the primate family tree, which diverged approximately 40 million years ago into a hominid branch containing among others familiar species such as the gorilla and chimpanzee. The human branch diverged yet further from the other primate cousins approximately 5 million years ago. From our limb of this tree, our human ancestors that preceded us, as well as our living cousins who evolved in parallel with us, share some interesting differences. One of the major developments occurring during our evolution as a potentially long-lived species has been the enlargement of our brain compared to other primates. This enlargement should not be considered in terms of simply brain size alone, but scaled relative to body size. When one considers this scaling factor, in fact, we have the largest brain to body size relationship of any primates and probably our own early ancestors. For example the chimpanzee has a brain which is three times smaller than the human brain. What is of further considerable interest in this development is the significant correlation of body scaled brain size with longevity.

What has accounted for this evolution toward a larger brain with a potential for a longer life? Perhaps the most prominent theory, which I favor, is the social brain hypothesis. That is that our species evolved mechanisms for survival based on solving specific environmental problems or pressures. Those in our line of development or evolution gained a survival advantage by developing social networks and cooperative cultures. This theory predicts that those species that develop effective social structures might have uniquely developed brains as a consequence. The brain changes therefore resulted in larger brains to take on new functions. It must be emphasized that it is not the absolute size of the brain that is important. It is the overall need for a larger brain to effect alterations in functional abilities of the brain that is key. Thus for example, if one looks at group size as a measure of social interaction among primate species, there is no significant relationship between group size and the weight or volume of the brain. However, if one looks at the special part of the brain, that is, the isocortex (also called the neocortex), there is a significant relationship between social group size in primates and the volume of the isocortex. In fact, longevity has a much stronger association with the volume of the brain, in particular the isocortex, than social group size alone. This evolutionary enlargement of the isocortex then forms a useful focus for further exploration as to what genes we may incidentally carry that promote the healthy aging of brains.

Remembering that brain expansion and longevity is a very recent phenomenon, one must be constantly reminded that there are no genes for centenarians, per se, but what we are really observing today is the result of genes that evolved to promote successful survival of our species as younger individuals. These genetic pressures are operating only during the period where major social and environmental forces are in play, particularly centered around reproduction and parenting of offspring until they can be independent. The relationship between brain size and body weight among species in terms of primates having a larger brain-body aspect is present in fetal individuals as well. This emphasizes that genes that are important for healthy brain survival are present during the earliest beginnings of our lives.

Knowing that there may be a link between the evolution of a bigger brain and longevity, might this lead us closer to a specific set of identified genes? We have all seen the front page headlines announcing the sequencing of the human genetic code. Certainly this is only the beginning of our understanding of our genetic endowment. However, this does raise the possibility of finally being able to uncover genes that may play a role and result in a healthy aging brain. If one were to focus on those genes that might lead to healthy aging of our brain, I would suggest that the place to look is among the genes that must be part of the program that required socialization and group cooperation for successful survival. As a response to this adaptation, these genes have evolved to function, alter or expand our isocortex under environmental change occurring over the years of hominid history. They are also the genes that happen now in our new environment of the past century, to permit a longer life span with an intact brain. They may not be common or turned on for our entire life-span. Since the age of onset of dementia is so variable, the gene actions may simply control the timing of a key process involved early in brain development which then “poops out” at later ages, heralding the onset of cognitive decline. Whether there are some rare genes that exist that have evolved such that 1% or less of the very elderly still maintains exceptional cognition is unknown, but still quite plausible, and I think worthy of our research efforts. What we learn, as is so often the case in genetics, is that genes found among rare individuals may allow us to apply that information to the rest of us who have the rather average complement of genes.

The prospect of finding these genes in our lifetime (depending on your current age) is not unreasonable. Thus for example, we currently know that there are genes responsible for specific folding of our isocortex, that evolved relatively recently, allowing our expanded brain to fit into a limited cranium or skull (a development presumably needed so that a large fetal brain could fit through the narrow birth canal). It is not beyond reason to consider that these "brain folding genes" may be pleiotrophic themselves and at later ages in our current environment result in relatively preserved brain function well downstream in our current life cycle. Alternatively, there may be other closely linked or neighbor-genes acting as passengers or "tag along genes" that are linked to our brain development and when placed in our current environment preserve brain function over a long lifetime. Clearly these are just examples and there are thousands of other genes that may play a role. But just a few decades ago not many people would have thought that we would be standing on the threshold of specifying any of these genes, let alone thinking about how this knowledge may affect our aging species in the new century.

With this new knowledge we will for the first time have the tools to significantly affect our cognitive destiny. So when asked if we might all someday live to be 100 and cognitively intact I think yes, not only is this possible, but this may become the rule rather than the exception. Is this desirable? Like all new knowledge it depends on your perspective. Certainly the prospect of many more active, functional people at advanced ages will have a tremendous impact on our society, profoundly affecting attitudes toward work and leisure. Of course such a demographic shift may also have the potential to create great upheaval as the distribution of resources and wealth may need to be redistributed along new lines. Ironically, those reading this article today despite living longer than their preceding generation will likely not live long enough to fully know how these demographic shifts will transform society. It is only our children's generation that may live to see the results of this new chapter in human history.