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Puett, David Ph.D.

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doi: 10.1249/FIT.0000000000000360
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It is a truism that humans, like all other organisms, age and that the aging process is accompanied by decreased cognitive ability, diminished physical strength, the onset of chronic diseases, and many more deleterious changes. Within the past few decades, a relatively new field, geroscience, has emerged that seeks to elucidate at the molecular, cellular, and organismal levels the reasons for aging, encompassing basic and applied research. The overall goal is not necessarily to increase longevity but rather to understand the drivers of this natural process and to apply the findings to promote healthier aging. The aim of this article is to present the main drivers of aging, along with proven and potential interventions to minimize the adverse alterations and improve healthspan. Furthermore, the increased incidence of frailty and chronic diseases that occur with advancing chronological age will be addressed.

The aim of this article is to present the main drivers of aging along with proven and potential interventions to minimize the adverse alterations and improve healthspan. Furthermore, the increased incidence of frailty and chronic diseases that occur with advancing chronological age will be addressed.

Because the literature on the topic of aging is growing exponentially, including results of basic research and translational intervention strategies, space limitations prohibit a thorough review; thus, only selected representative references are given.


Everyone begins the journey of living after natural fertilization or some form of assisted reproductive technology such as in vitro fertilization. With but a few rare exceptions involving genetic abnormalities, every human starts with a nuclear genome of 46 chromosomes, including two sex chromosomes (X and Y) and also a mitochondrial genome inherited from the mother only. In the wondrous union of a single sperm (22, X or 22, Y) fertilizing an egg (or oocyte, 22, X), the resulting zygote will be either 46, XX or 46, XY, a genetic female or male, respectively. The information stored in these 46 chromosomes and in the mitochondrial genome is responsible, aside from important environmental influences, for each person’s individuality, for the growth and development that occurs in utero and after birth, and later, after alterations from internal and external sources, for many aspects of the aging process.

If one views the journey of life from the beginning to the end and plots some measure of physical and/or mental performance over the lifespan, the curve would appear as shown in Figure 1. There is a gradual increase in performance that reaches a peak at some chronological age range and then declines because of impaired performance of physical and mental status as well as the onset of chronic diseases. The concept of “compression of morbidity” was introduced nearly 40 years ago (1) and has had a major impact on the development of geroscience. The premise is simple: if the time of the gradual decline in performance could be minimized, then one would live a healthier life until death. Geroscience became accepted as a well-grounded scientific discipline when it was demonstrated that (a) there are identifiable and measurable molecular and cellular changes responsible for aging and (b) certain interventions can delay the biological aging process and the onset of chronic diseases. The concept that biological aging, unlike chronological aging, is malleable represented a significant breakthrough in aging research.

Figure 1
Figure 1:
Hypothetical plot of performance (physical and mental) on the y-axis versus the age of an individual on the x-axis from birth to death. At some age range, there is an expected maximum in physical performance and mental cognition, after which both decline, although not necessarily at equal rates as implied in the figure. The concept of compression of morbidity (designated as COM in the figure) is to intervene with strategies that shift the period of decline to later years. Importantly, the desire is to achieve a healthier lifespan, not necessarily increased longevity.

Geroscience became accepted as a well-grounded scientific discipline when it was demonstrated that (a) there are identifiable and measurable molecular and cellular changes responsible for aging and (b) certain interventions can delay the biological aging process and the onset of chronic diseases. The concept that biological aging, unlike chronological aging, is malleable represented a significant breakthrough in aging research.

There is urgency in this undertaking because today, the number of people 65 and older in the United States is approximately 15%, and in less than 15 years, one in five Americans (20%) will fall into this category.


The field of geroscience has elucidated a number of drivers responsible for aging (2,3), and those most carefully investigated and deemed highly important by the author are summarized in the Table and briefly discussed later. The drivers listed are not all independent of each other; indeed, there can be complex interactions between the drivers such that one driver can profoundly influence other drivers. Each, however, is discussed separately to emphasize its importance. These drivers are known to be responsible for, or at least significantly contribute to, most of the functional decline in physical and cognitive abilities, the devastating chronic diseases, and frailty experienced by the aging population. Individuals participate in fitness programs for laudable reasons, including muscle tone, strength, flexibility, weight control, and balance, to name but a few. Most importantly, however, it is the regimens led and taught by sports physiologists and exercise trainers for the aging population that are producing nonvisible positive changes for their clients on the cellular and molecular levels.

Drivers of Aging*

Genomic Changes

The human nuclear genome contains 3 billion base pairs of deoxyribonucleic acid (DNA) (Figure 2) as well as a smaller mitochondrial genome containing more than 16,500 base pairs. Our DNA constitutes our inheritance and defines in large part who we are, how we look, and how we age, this being accomplished with just four different chemical bases (Figure 2 legend). A typical drawing of a chromosome that becomes magnified to reveal smaller units, terminating with a sketch of the well-known Watson-Crick double-strand DNA, is shown in Figure 2. Of the total DNA in the human genome, only a relatively small fraction encodes for proteins, the components of cells responsible for maintaining their basic structure, coordinating and implementing function, and regulating gene activity. Each cell division requires accurate copying of more than 3 billion base pairs of DNA — truly a Herculean task. To ensure fidelity in this important step, cells have evolved a sophisticated system for copying, proofreading, and correcting errors. These processes, however, are not 100% accurate and effective. In time, mistakes can and do accumulate. In addition, environmental factors, including chemical mutagens, ultraviolet and ionizing radiation, pollutants, and many others can lead to modifications in DNA; for example, changes of one base to another, deletion of bases, transference of a segment of the DNA from one location to another, and others. With advancing age, these small alterations in the genetic material can produce deleterious changes that can negatively impact many bodily functions and are responsible in large part for the development of chronic diseases.

Figure 2
Figure 2:
Sketch of a typical chromosome (lower central portion of figure), of which 46 are present in humans: 44 autosomes and 2 sex chromosomes, either XX (female) or XY (male). The ends of each chromosome contain telomeres that aid in preserving the integrity of the chromosome and are necessary for proper duplication during cell division. Magnification of a section of the chromosome would show a chromatin fiber, while further magnification would enable us to see strands of DNA, indicated as lines, encircling discs. As magnification is increased, the discs take the shape of tightly packed spheres; these are proteins known as histones. Increasing magnification shows an antiparallel double-strand DNA helix that contains four bases: adenine (A), thymine (T), cytosine (C), and guanine (G). A base pair is either A-T or G-C. The epigenome refers to chemical substituents that are attached to either the DNA or the histones. The sequential order of the four bases in DNA defines a gene, and there are believed to be some 22,000 genes encoding proteins. The processes of alternative splicing and posttranslational modifications, however, increase the total number of proteins many fold. Most human genes are composed of introns and exons, only the latter giving rise to proteins. (Figure courtesy of Darryl Leja of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.)

Epigenetic Changes

The epigenome refers to the chemical attachments that are linked to both DNA and the associated proteins (Figure 2). Although these chemical additions are not part of genetic coding, they nonetheless are important in influencing the accessibility of genes to be read and then translated into protein. Like the genome, the epigenome can be modified by environmental factors and can undergo changes that affect the aging process.

Telomeric Changes

Telomeres are structures composed of DNA and protein that are located at the end of chromosomes (Figure 3) and function to preserve chromosomal structure, much like the plastic tabs at the end of a shoelace prevent the unraveling of the lace itself. With each cell division, telomeres decrease in length and, when depleted, the cells harboring these shortened telomeres cease division and either die via cell suicide (a process termed apoptosis) or enter a state termed senescence (see next section). In aging, the decrease in telomere length is accentuated by genomic and epigenomic alterations and a decline in adult stem cell function as discussed later.

Figure 3
Figure 3:
Sketch of telomeres. Composed of DNA and proteins, telomeres are located at the ends of chromosomes and function to protect genomic integrity. (Figure courtesy of Wikimedia Commons with permission granted to reprint.)

Cell Senescence

It has been known for many years that cells have a finite lifespan. When cells stop dividing but do not die, they enter a state of senescence. Cells in this state may secrete numerous factors that can negatively affect neighboring cells and tissues. Senescent cells accumulate in aging tissues and can lead to organ failure. It is known that there are many causes of senescence, including telomere shortening, genomic instability, epigenomic changes, and other drivers of aging.

Decline in Stem Cell Regeneration

After fertilization, cell division occurs, and special attention is directed to the developing embryo at day 5 postfertilization, denoted as a blastocyst, the source of embryonic stem cells (ESCs) (Figure 4). After implantation into the uterus some 8 to 9 days postfertilization, the embryo undergoes rapid development and growth in utero, followed in 9 months by birth. These remarkable changes arise from the information encoded in the genome, present in the ESCs. These stem cells undergo differentiation (cell specialization) and growth (cell division) to form the brain, skeletal muscle, the heart, lungs, kidneys, bone, etc. They also lead to the development of adult stem cells that appear in each of the tissues and organs. The role of these adult stem cells is to replenish dying cells as needed; thus, their importance cannot be overemphasized. With increasing age, adverse genomic, epigenomic, and other alterations will, however, diminish the effectiveness of the adult tissue-specific stem cells, thus leading to a decline in particular organs.

Figure 4
Figure 4:
Micrograph of a day-5 blastocyst (5 days postfertilization) showing the trophoblast, or trophectoderm (approximately 200 cells around the periphery surrounding a fluid-filled cavity), and the inner cell mass (some 30 to 34 tightly packed cells shown in the upper portion at approximately a 12:30 position). The cells in the inner cell mass are human embryonic stem cells that, through differentiation and division, will eventually form all 200-plus types of cells in the human body, which contains an estimated 30 trillion cells. (Figure courtesy of Wikimedia Commons and in the public domain because it came from the National Institutes of Health (34), to which the interested reader is referred for additional information on stem cells. The image was taken and posted by Mr. J. Conaghan.)


Environmental pathogens such as bacteria and viruses trigger an inflammatory response in an attempt to rid the body of the offending organisms. In aging, the response may be normal, but it also can be reduced or exaggerated. The inflammatory response may not terminate as it should, but rather persist, contributing to chronic diseases.

Mitochondrial Alterations

Mitochondria are cellular components that have an important role in metabolism, namely, that of producing adenosine triphosphate (ATP), which can be considered the currency in cellular energetics. Mitochondria are adversely affected by the aging process. The ability of mitochondria to make ATP is compromised, contributing to the age-dependent loss of muscle mass and function.

Diminished Protein Homeostasis

The successful coordination of intracellular and extracellular functions requires the interplay of numerous proteins operating in cooperative and interacting networks. Alterations in genomic stability, epigenomic fidelity, and others can lead to diminished protein activity, unbalanced pathways in metabolism, and many more deleterious effects that diminish cell and thus, organ function, contributing to some of the adverse effects of aging.

Reactive Oxygen and Nitrogen Species as Stressors

Throughout life, everyone is exposed to external stressors, both psychological and physiological; for example, ionizing radiation, ultraviolet light, toxins from the environment, highly reactive free radicals, and others, that over time contribute to aging. In addition, reactive oxygen and nitrogen species (internal free radicals) are produced during metabolism, in large part from mitochondrial production of ATP, and can act as cellular stressors. These reactive species impact many cellular processes: some positive, such as defense against bacteria, viruses, and fungi, and many negative, such as genomic, epigenomic, and stem cell alterations, thus becoming a factor as one ages.


There are many physiological and neurological changes accompanying aging, and four of these will be briefly discussed: frailty and three of the chronic diseases, heart disease, cancer, and Alzheimer’s disease (AD). Frailty is characterized by weakness (attributed in part to sarcopenia, i.e., muscle atrophy, and reduced muscle function), slowness, exhaustion, a low activity level, an unintentional weight loss, and often, osteoporosis (4). Frailty affects some 10% of the population, and for adults older than 85 years, the prevalence is approximately 25%.

Aging is a major risk factor for all chronic diseases as exemplified by the statistic that 70% of individuals older than 65 have two or more chronic diseases (5). The six major causes of death in the U.S. population (from 2014 data, the most recent year for which accurate results are available) were, in decreasing order, heart disease, cancer, chronic lower respiratory diseases, accidents, stroke, and AD (6). Heart disease, cancer, and AD were responsible for the deaths of 614,348, 591,699, and 93,541 Americans, respectively. Aside from unintentional accidents and infectious disease, older Americans die from these and other chronic diseases. Figure 5 shows a plot of mortality versus age for three of the chronic diseases, heart disease, cancer, and AD. For heart disease and cancer (and most of the other chronic diseases), mortality is relatively low until approximately 50 to 60 years and then increases exponentially. With AD, mortality is low until approximately 65 years, after which there also is an exponential increase in the number of deaths.

Figure 5
Figure 5:
Mortality (deaths per 100,000) in the United States versus age. These results demonstrate that aging is a major risk factor for the three chronic diseases depicted, and although not shown, the same conclusion would be drawn if all the chronic diseases were so plotted. The numbers were taken from the U.S. Centers for Disease Control and Prevention website (6) and refer to 2014, the most recent year for which accurate data are available. The ages are reported by the CDC in 5-year increments, and an average (2.5 years) was taken to make the figure.

Some 70% of Americans ages 60 to 79 have some form of heart disease, a number that increases to approximately 80% for those age 80 years and older (7). This can be attributed to most, if not all, of the drivers listed in the Table. Cancer represents many diseases and has many causes (36), most of which also arise from the drivers of aging. The American Cancer Society estimated there would be nearly 1.7 million cases of new cancer in 2017 and more than 600,000 cancer-related deaths (8). Some 5.5 million Americans have AD, and of these, 5.3 million are age 65 and older. Of those individuals with AD, approximately 82% are 75 and older (9).


Proven Interventions

In view of the overwhelming statistics mentioned previously, there is an urgent need to translate laboratory-based findings on the drivers of aging into practical interventions. Because the drivers of aging have been shown to cause chronic diseases, frailty, sarcopenia, dementia, and other adverse conditions, exhaustive investigations have been conducted on ways to ameliorate, or at least lessen, the impact of these devastating, by and large end-of-life events. The best known and documented strategy encompasses physical activity and exercise (physical activity

Because the drivers of aging have been shown to cause chronic diseases, frailty, sarcopenia, dementia, and other adverse conditions, exhaustive investigations have been conducted on ways to ameliorate, or at least lessen, the impact of these devastating, by and large end-of-life events. The best known and documented strategy encompasses physical activity and exercise…

being thought of as any movement by the body that requires contraction of skeletal muscles resulting in increased calorie usage over that required for resting energy and exercise referring to a more structured program designed to maintain or improve one or various components of fitness that can involve resistance, aerobic, or flexibility), or preferably, a combination of these (10).

The American College of Sports Medicine has published a position stand on exercise programs for older adults (11), and sports physiologists and exercise trainers have directed their clients along this or similar regimens for years (Sidebar 1). The results from numerous scientific studies are overwhelmingly positive and indisputable regarding the beneficial effects of physical activity and exercise in the aging population, resulting in measurable and highly positive outcomes, both on physical fitness and cognition, and diminishing many of the adverse effects of aging (12).

Sidebar 1

General Fitness Program for an Older Population

Several agencies have recommended fitness programs for the aging population (10–12,35), and an amalgamated summary is given here for the suggested regimen. If not in place already, a fitness center with a reasonable number of geriatric clients should initiate and continue such a program, and such an offering may improve the number of membership seniors. To accommodate clients with restricted mobility or those with health conditions that prohibit a full program, adjustments can be made as appropriate. The target of such a regimen is to minimize as fully as possible the adverse effects of the drivers of aging, and it is now well documented that these and other physical activity and exercise programs are effective in this regard.

  1. Moderate-intensity aerobic exercise for 150 min/wk with sessions lasting 30 to 60 minutes (3 or 5 d/wk). High-intensity aerobic activities should be at least 10 minutes in duration and total 75 min/wk for a minimum of 3 d/wk. A combination of moderate and vigorous-intensity exercise 3 to 5 d/wk often is effective. Sessions could begin at 10 to 20 minutes’ duration and then be gradually increased to the desired maximum. Goals will differ depending on the ability of participants.
  2. The major muscle groups should be engaged in resistance training 2 or 3 d/wk, with each training exercise involving 2 to 4 sets with 8 to 12 repetitions per set and a 2- to 3-minute rest interval between sets. Weight-bearing calisthenics, stair climbing, and other activities that use the major muscle groups can be substituted if necessary.
  3. Flexibility and balance exercises should be part of the program and can be incorporated into the sessions on aerobic exercises and/or resistance training a minimum of 2 or 3 d/wk. It is recommended that each joint receive a total of 1-minute flexibility exercise.

The instructor should emphasize that these programs be augmented with physical activity and reduced sitting time throughout the day. A good guideline for those capable is a minimum of 10,000 steps per day.

There is strong backing for an important role of physical activity and exercise in maintaining telomere length (13,14) (Sidebar 2) and in reducing the onset of frailty (4,5,14,15) (Sidebar 3) and chronic diseases (2,16), including heart disease (2,17), cancer (18), and AD (19–21). Today, modern scientific studies have the capability of measuring molecular and cellular changes, thus adding considerable specificity to the outcomes after particular programs. Such detailed molecular and cellular studies provide novel and useful information, but also present enormous challenges in interpretation of the massive amounts of data forthcoming. For example, one recent study focused on changes in skeletal muscle gene expression after endurance training. The investigators determined that the expressions of more than 2,600 different genes, that is, more than 10% of the genes comprising the human genome, were altered after the training regimen (22). Elucidation of the gene products has provided considerable information on the myriad skeletal muscle responses to endurance training.

Sidebar 2

Exercise and Telomerase Activity/Telomere Length

Telomeres (repeating sequences of DNA and six proteins) function to maintain chromosomal stability. A survey of the effects of exercise on telomere length and telomerase activity (telomerase being the enzyme responsible for maintaining telomere length) has been conducted (13), with the following aerobic exercises being shown to be effective. The chosen moderate- or high-intensity aerobic exercise should be performed 3 to 4 times per week for a minimum of 6 months, and each performance should be preceded by a 10-minute warm-up and a shorter cool-down. [N.B. Use of a stationary cycle is of course beneficial.]

  1. Walking: Four intervals of fast walk with each interval involving a fast walk for 3 minutes (at a level of 6 to 7 on an exertion scale of 1 to 10) followed by a gentle stroll of 3 minutes. OR
  2. Running: Four intervals of fast running with each interval involving a fast run for 3 minutes and then an easy run for 3 minutes. OR
  3. Walking or Running: Three times per week of either a fast walk or run at approximately 60% of maximum ability for 40 minutes.
Sidebar 3

Overcoming, Minimizing, or at Least Delaying Frailty

In fitness centers with a reasonable number of seniors exhibiting early signs of frailty, or in a center that would invite seniors from the community or home-dwelling venues, offer a 6-month program that has been shown in a well-controlled study to reverse many aspects of frailty and to improve physical function, as well as emotional, cognitive, and social network determinations (15). A flyer or seminar could be made available that encourages attendance of individuals in retirement centers, seniors in day centers, and anyone older than 50 years who is interested.

The seminar or flyer should briefly review the statistics of frailty (10% of adults older than 65 years and increasing to 25% or more of adults older than 85) and some of the clinical characteristics associated with frailty: weight loss, slowness in movement, exhaustion, low energy expenditure, and weakness, for example, in a test of grip strength. Emphasize the adverse effects of frailty: falls, hospitalization, nursing home admission, and an expected progression of the disability. Speak with assertiveness that, without question, physical activity and exercise have been demonstrated to prevent or delay the onset of frailty (4,15).

The following 6-month multicomponent exercise intervention meets 5 d/wk, with 65- to 70-minute sessions each day, and has been shown to reverse many symptoms of frailty. Each session involves a 10-minute warm-up, 10 to 15 minutes of proprioception and balance exercises, 40 minutes of aerobic training, 2 d/wk of strength training with resistance bands, and 5 minutes of stretching.

Monday, Wednesday, Friday: 10 minutes warm-up with stretching; 10 minutes proprioception/balance exercises; 40 minutes involving mild aerobic exercise interspersed with arm movements: 5 minutes walking, 20 reps arm vertical movements, 10 minutes walking, 20 reps arm rotations, walking or some stair climbing until 40 minutes is reached; 5 minutes stretching.

Tuesday, Thursday: The same as MWF except substitute aerobic exercises with some form of strength training, for example with elastic bands and miniball and small-ball squeezing.

Months 1 and 2: 25% maximum heart rate (HRmax); months 3 and 4: 50% HRmax; months 5 and 6: 75% HRmax.

Reps can be altered after month 1, and more information on the specific warm-up, proprioception/balance, stretching, and aerobic and strength training can be found in the original article (15).

Another recent study was conducted on two age groups, persons age 18 to 30 years and 65 to 80 years (23), but the following discussion is limited to the older population. Using sophisticated molecular and cellular measurements, it was demonstrated that the age-dependent decline in skeletal muscle protein synthesis and mitochondrial number/function can at least be partially reversed by exercise, thus enhancing muscle hypertrophy and cellular energetics, respectively. Improvements were found in fat-free body mass, insulin sensitivity, mitochondrial respiration, cardiorespiratory fitness, increased mitochondrial and skeletal muscle protein biosynthesis, and increased messenger ribonucleic acid (mRNA) expression, mRNAs being intermediates in the production of proteins from genes. Sidebar 4 summarizes the 12-week training modalities used. The loss of muscle mass (atrophy) and function is a hallmark of aging, due in part to reduced muscle stem cell number, arising from DNA damage, epigenetic changes, accumulation of senescent cells, and alterations in mitochondria and protein homeostasis. These age-dependent changes lead to the loss of types I and II myofibers, as well as the atrophy of type II myofibers, accounting for much of the observed muscle loss. Aerobic and resistance training have a multitude of positive effects on muscle, including, but certainly not limited to, metabolic alterations, vascular regeneration, enhanced mitochondrial function, ribosome biogenesis, enhancement of insulin sensitivity (in part by increasing the number of glucose transporters responsible for relocating glucose from the blood into muscle cells), and hypertrophy of fast-twitch myofibers (predominantly type II).

Sidebar 4

Training Modalities to Enhance Lean Body Mass, Insulin Sensitivity, Mitochondrial Respiration, and Cardiorespiratory Fitness in a Population Age 65 to 80 Years

The following 12-week exercise regimens, high-intensity aerobic interval training, resistance training, and combined high-intensity aerobic interval training and resistance training, were found to be effective in overcoming and reversing a number of age-dependent parameters (23). These protocols, modified as necessary depending on the equipment and measuring devices available, can be implemented after a short introduction to the overall program and the proven outcomes (see text). The exercise physiologist or fitness trainer leading the group should emphasize the importance of overcoming and partially reversing the age-dependent decline in mitochondrial function, explaining that mitochondria are responsible for the great majority of ATP production in the body, ATP being required for the production of cellular energy. After a 10-minute warm-up on a treadmill, elliptical machine, or bike, participants would adhere to the following regimen, always with the instructor present.

High-Intensity Aerobic Interval Training (12 weeks)

Five d/wk with 3 days (MWF) of intervals using an electronically braked cycle ergometer and 2 days (TuTh) of treadmill (motorized) walking.

MWF, stationary cycle: 10-minute warm-up, then four cycles of 4-minute high-intensity intervals (>90%) with each followed by a 3-minute rest with light pedaling at zero load, and then a 5-minute cool-down.

TuTh, treadmill: 10-minute warm-up followed by 45 minutes at a walking pace of 2 to 4 mph at incline at 70% VO2peak, and then a 5-minute cool down.

Resistance Training (12 weeks)

Four d/wk with 2 days (MTh) of lower body exercises and 2 days (TuF) of upper body exercises. After appropriate instruction on lifting technique, the participants perform 8 to 12 repetitions per exercise with a 1-minute rest between sets.

Week 1: two sets of each exercise; week 2: three sets of each exercise; weeks 3 to 12: four sets of each exercise.

When good form can be maintained for four sets, weights should be increased.

MTh: calf raise, leg press, lunge, leg extension, leg curl, and abdominal crunch.

TuF: horizontal chest press, incline chest press, biceps curl, triceps extension, lat pull-down, seated row, and lateral raise.

Combined Training (12 weeks)

Five d/wk (M–F) beginning with a 5-minute warm-up that is followed by 30 minutes of cycling each day and then 30 minutes of weight lifting on 4 days.

Cycling: 20 minutes each of 5 days at 70% VO2peak followed by a 5-minute cool-down.

Weight lifting: 30 minutes each of 4 days with lower body (abdominal crunch, leg press, leg extension, and leg curls) on MTh and upper body (biceps curl, triceps extension, chest press, and lat pull-down) on TuF.

Numerous studies have been reported showing the benefits of physical activity and exercise in delaying or lessening dementia and improving cognitive outcomes in patients with AD. In one recent investigation, improvements were noted in cardiorespiratory fitness and memory performance, along with a reduction in hippocampal atrophy, after a 26-week aerobic exercise program for individuals with early AD (24). In another study of patients with early AD, it was found that a 16-week aerobic exercise program led to improvements in cardiorespiratory function, single-task physical performance, dual-task performance, and exercise self-efficacy (25). The two programs are summarized in Sidebar 5. There is some debate regarding the exact mechanisms by which physical activity and exercise benefit dementia patients, but one pathway is emerging — namely, that of increased brain neurotrophins, proteins responsible for stimulating neuronal growth and maintaining brain mass and function. These proteins, and particularly brain-derived neurotrophic factor, are active in the hippocampus and cortex, regions of the brain important in cognition and memory. A recent finding suggested that the production of β-hydroxybuterate, one of the two ketone bodies made by the liver, which supplements glucose for the brain during exercise, increases the level of brain-derived neurotrophic factor (21). Much research remains to be done, but the possibilities are exciting for new breakthroughs in this area.

Sidebar 5

Aerobic Exercises for Individuals with Mild (Early) AD

Various studies have demonstrated that aerobic exercise is beneficial to individuals with early AD. {If desired, VO2peak and maximum heart rate (HRmax) can be measured before and after the program; if these parameters are not readily measureable, then estimates can be made: HRmax (220 − age) or [208 − (0.7 × age)], and VO2peak (HRmax ÷ HRresting).} Caution is recommended in working with adults having early AD, and the approval of a physician should precede participants (either home dwelling or community dwelling) beginning an extended aerobic regimen. The following two programs, A (24) and B (25), have been documented to have beneficial effects with individuals having mild AD. In addition to programs such as these that involve physical exertion, studies have shown that cognitive exercises also are effective in delaying or minimizing the onset and debilitating effects of AD.

A. Exercise training included 20 minutes on a treadmill at 0% grade and 1.7 mph followed by an increase in both grade and speed to yield 50% to 70% HRmax. When the class is capable of achieving 40 minutes of continuous exercise, the 26-week program can begin. The workload (both speed and grade) can be individualized, and the exercise duration of 150 min/wk can be distributed over three to five sessions, with each session having warm-up and cool-down periods of 5 minutes (24).

Weeks 1 to 4: achieve a heart rate zone of 40% to 55% HR reserve (HRmax − HRrest).

Weeks 5 to 18: ibid. 50% to 65% HR reserve.

Weeks 19 to 26: ibid. 60% to 75% HR reserve.

B. Weeks 1 to 4: Introduction to aerobic training and strength training of lower extremity muscles (60-minute sessions 3 times per week).

Weeks 5 to 16: Moderate-to-high-intensity aerobic exercise on an ergometer bicycle, cross-trainer, and treadmill at 70% to 80% HRmax done in three periods of 10 minutes each with rests of 2 to 5 minutes in between (25).

A good diet, recommended for everyone, is particularly important for the aging population. It has been shown that a Mediterranean diet, as well as a diet promoting consumption of antioxidant-rich and plant-derived foods, aids in maintaining telomere length (26,27). Importantly, a healthy lifestyle is essential to maximize the healthspan. This includes diet, physical activity, and exercise while minimizing the exposure to and consumption of hazardous environmental agents. Although sunlight is necessary for vitamin D metabolism, care should be taken to avoid overexposure.

Emerging Interventions

There is considerable promise in the possibility of stem cell replacement to replenish failing organs. After parental permission, human ESCs have been obtained from nonimplanted day-5 blastocysts that would otherwise have been discarded after successful in vitro fertilization. Because the use of these ESCs has raised many moral, ethical, and religious concerns, recent studies have been conducted showing that induced pluripotent stem cells (cells that behave like ESCs) can be obtained by reprogramming adult terminally differentiated cells such as fibroblasts. These, in turn, can be further differentiated into tissue-specific cells (28,29). It also has been shown that one class of adult cells can be directly differentiated into another class of cells (29). Thus, from these remarkable and exciting observations, it may become possible to replace failing cells in specific tissues without resorting to day-5 blastocysts.

Another emerging area of interest in delaying many of the deleterious effects of aging is that of pharmacological intervention (30). The approach is to identify a drug(s) that delays or deters several of the major chronic diseases. Two compounds in particular, metformin (31), widely used in the treatment of type 2 diabetes, and rapamycin (32), currently used as an immunosuppressant and anticancer agent, have generated considerable excitement as possible interventions to delay the onset of chronic diseases and promote compression of morbidity. Both, however, require considerable research as to efficacy. Lastly, although directed against one chronic disease only, a recent report showed that a monoclonal antibody reduced plaques in patients with AD and may lead to improved cognition (33).


In the past few decades, we have witnessed an unprecedented increase in our knowledge of aging, and the relatively new field of geroscience is now in full swing and tackling many problems in a multidisciplinary manner. This knowledge, boosted by the application of sophisticated techniques in molecular and cellular biology, have opened entirely new avenues of investigation into the drivers of aging, and the emerging information will enable specificity into different approaches for minimizing or delaying the inevitable decline in physical and cognitive abilities with advancing chronological years. Fitness providers and clients have known for years that physical activity and exercise have obvious benefits to cardiorespiratory and muscular systems, and we now know that these same regimens can minimize the impact of the drivers of aging on the molecular and cellular levels. The future in aging research, coupled with the resulting practical applications forthcoming from myriad studies, bodes well!

Research has shown that one should be committed to daily physical activity and a well-balanced exercise regimen, healthy diet, and healthy lifestyle. A saying attributed to the Greek physician, Hippocrates, in approximately 450 BCE, holds true today as it did some two and a half millennia ago: “If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health.”


Researchers in geroscience have identified several molecular and cellular drivers that are responsible for the aging phenotype. It has been conclusively demonstrated that physical activity and a well-structured exercise regimen can overcome many of the deleterious effects of aging. Although there is interest in the possibility of pharmacological intervention to delay or obviate the onset of chronic diseases, considerable research and clinical trials are necessary before it is known whether they will prove beneficial or not.


The author thanks Jennifer Rehm for helpful advice and Connor Puett for his invaluable assistance.


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    Drivers of Aging; Geroscience; Important Role of Exercise; Molecular/Cellular Aspects of Aging; Potential Pharmacological Interventions

    © 2018 American College of Sports Medicine.