Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. pe17
[DOI: 10.1126/sageke.2006.10.pe17]


Developing a Research Agenda in Biogerontology: Physiological Systems

Jill L. Carrington, and Francis L. Bellino

The authors are in the Biology of Aging Program at the National Institute on Aging, Bethesda, MD 20892, USA. E-mail: carringtonj{at} (J.L.C.)

Key Words: prostate • ovary • testis • kidney • bone • skeletal muscle • stem cells • oxidative stress • cellular senescence • apoptosis • grant funding • aging-related research priorities


Recently, SAGE KE published a Perspective by Huber Warner that outlined several aspects of his experiences as a program administrator in the Biology of Aging Program (BAP) at the National Institute on Aging (NIA) during a time when biology of aging research was undergoing a transition from descriptive aging-related research to mechanistic studies. A number of biological processes were discussed that currently are thought to be important in cell damage with age and in the determination of organism life span as a result of genetic influences and macromolecular damage. These processes include cell senescence, cell death, oxidative stress, the functioning of longevity genes, and caloric restriction. The role of program staff in encouraging and supporting research in each of these areas, prominent initiatives, and important advances in aging-related research were discussed in this first Perspective on Developing a Research Agenda in Biogerontology. We write this as a companion article to similarly describe the recent years of the efforts of BAP, NIA, in support of research on aging physiological systems. Because the original article by Warner described the early formation of NIA and early program activities to promote biology of aging research, we will not repeat those aspects here, but refer the reader to that original article (1) and take as our jumping-off point the rationale and programmatic activities for support of research on aging physiological systems. Although space permits a few examples to illustrate supported areas of research, we cannot mention all of the many outstanding investigators and projects in this segment of aging-related research and apologize to the many we could not include.

A substantial effort within BAP at NIA is devoted to understanding how cells and organisms senesce (see "More Than a Sum of Our Cells") and how caloric restriction or other potential interventions extend life span (see "Craving an Answer"). The eventual aim of research in aging is to improve the health of an aging United States population. However, to achieve this goal, it is not enough to understand how an individual cell senesces, becomes apoptotic, or becomes dysfunctional with time. Rather, to understand how the function of the tissue and health of the organism are altered with age, it is necessary to understand the effects of an aged cell within the context of the tissue in which it resides and the age-altered milieu in the tissue. It is our purpose in this Perspective to describe areas of research that BAP at NIA has supported to link what is known about the cell biology and genetics of aging with the study of tissue and organ function.

Applying Aspects of Cellular Aging to the Biology of Tissue Aging

BAP has supported basic research on the biology of aging tissues through a variety of efforts. Support in this area extends back over 10 years. Increasing amounts of tissue-based research justified formation of the Systems Branch in 2000, with individual programs in cardiovascular biology, endocrinology, immunology, musculoskeletal biology, and physiology. Programmatic activity has focused on individual tissues but has also deliberately fostered integration of systems and integration across systems. This approach has been taken with the intent to accelerate progress in research in two areas of aging beyond what happens to individual cells or single tissues. Specifically, the goals are (i) to understand interacting tissues and systems and (ii) to deduce common underlying aging mechanisms that lead to altered function in physiological systems.

Below are some examples of current research in tissue/organ systems that parallel and extend the explorations of aging processes in isolated cells in culture. These studies apply concepts of cell senescence, cell death, and oxidative stress to research on aging of tissues and organisms. In addition to supporting research such as the examples below, BAP has organized and supported workshops to highlight both the basic science and clinical aspects of tissue aging. Examples include (i) the Functional Senescence workshop in 2001, (ii) a workshop on Extracellular Matrix and Aging Musculoskeletal System and Skin in 2002, (iii) the Immunology and Aging Workshop and several other immunology-related meetings and workshops between 2002 and 2005, (iv) the Biology of Aging Kidney Workshop in 2003, and (v) the Biology of the Perimenopause Workshop in 2004. Each of these workshops provided a forum for discussion and understanding of how aging processes lead to tissue pathology and loss of function.

Cell senescence in the prostate

Men experience a high probability of clinical and subclinical prostate-related problems as they grow older, most frequently prostate cancer and/or urinary retention associated with benign prostatic hyperplasia (BPH). Studies suggest that, in contrast to most body organs, the prostate gland continues to grow beyond puberty and may reach peak growth rates in middle-aged men, with high rates continuing into old age. Very little is known, however, about what regulates this age-related growth process and about the relation of this growth process to the growth-related prostate problems of BPH and cancer. To encourage research into understanding the biological mechanisms underlying prostate growth processes responsible for the increasing incidence and prevalence of prostate-related health problems in older ages, NIA issued a program announcement (PA) in 1993: PA-93-052--"Prostate growth in older men: Age-dependent mechanisms," cosponsored by the National Institute on Diabetes, Digestive, and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI). To further encourage research in this important area, NIA, with cosponsorship from NIDDK, NCI, and the National Institute of Environmental Health Sciences (NIEHS), organized a workshop in 2000 on "Prostate Growth and Aging" (2). At that workshop, Dr. Judith Campisi described her hypothesis that senescent cells in tissue may modify the local environment of normal cells in a manner that stimulates proliferation of these normal cells, or even that permits proliferation of precancerous cells residing in the tissue (see "Faustian Bargain" and "Led Astray"). Subsequently, an updated PA was issued in 2002 by NIA and cosponsored by NCI, NIDDK, and NIEHS, PA-02-116, "Age-related Prostate Growth: Biologic Mechanisms." This PA encouraged, in part, research on the role of cellular senescence in promoting age-related prostate growth.

In recent studies, senescent cells were identified in human BPH tissue and in serially passaged cultures of human prostate epithelial cells (3, 4) using the senescence-associated beta-galactosidase marker. There are reports of increased expression of specific genes in senescent prostate epithelial cells in culture. These include the gene encoding interleukin-1{alpha}, a regulator of fibroblast growth factor 7 secretion in prostate stromal cells that may in turn stimulate prostate epithelial cell proliferation (5), and the tumor suppressor gene p16/INK4a (6, 7). In addition, 15-lipoxygenase 2, an enzyme with restricted tissue expression, which is most abundantly expressed in adult human prostate but not in prostate cancer, can induce a senescence-like phenotype when stably transfected into cultured prostate cancer cells and is associated with senescence in cultured prostate epithelial cells and increased age in human prostate tissue (8). This newly emerging focus on senescent cells in the aging prostate appears to be a productive area for future research to understand how senescent cells can alter the prostatic environment to promote tissue growth or tumor formation.

Cell death: Delay in female reproductive aging by reducing apoptosis extends a healthy life span

NIA has had a long interest in understanding the biological and physiological basis for the menopausal process in women and the connections of that process with health problems and conditions associated with menopause in postmenopausal women. Before the 1990s, NIH had expressed little overt interest through proposed initiatives in understanding the menopausal process. In 1993, NIA led a group of NIH institutes and centers in sponsoring the NIH Workshop on Menopause. BAP organized a breakout session at that workshop on the Biology of Ovarian and Neuroendocrine Systems During the Menopausal Transition. After the workshop, NIA issued a request for applications (RFA) that formed the basis for the current Study of Women's Health Across the Nation (SWAN), a multiethnic, observational, longitudinal study of >3000 women from age 42 to 52. BAP subsequently issued two PAs: one in 1995--PA-95-006, "Biology of the menopause: Change of ovarian function," and one in 2001--PA-01-067, "Biology of the menopausal process and associated health conditions during and after menopause." A recent BAP-led RFA--AG-05-008, "Biology of the perimenopause: Impact on health and aging in non-reproductive somatic and neuronal tissues"--invited research applications to explore the role of changing hormonal levels and temporal patterns of hormonal expression that occur during perimenopause on pathophysiological processes associated with menopause.

The process of female reproductive aging is associated with the essentially complete loss of ovarian follicles, the ovarian structures containing oocytes. More than 99% of these follicles are lost over the life span by a process called atresia, whereas the remaining follicles are lost by ovulation. The process of follicular atresia, in turn, is driven by apoptotic cell death, a process in which the Bax gene plays a major role. Tilly and colleagues (9) explored ovarian follicle dynamics across the life span of Bax-/- mice, based on their hypothesis that such a transgenic animal may have reduced follicular atresia and thus a greater ovarian follicular endowment into older ages. Their hypothesis was confirmed by the documentation of substantially greater number of nonatretic follicles relative to wild type in the Bax-/- mice at 20 to 22 months of age, although the numbers of nonatretic follicles just after birth were not different. The older Bax-/- mice exhibited ovarian-steroid-driven uterine hypertrophy, contrasted with the uterine atrophy in age-matched wild-type mice. These results suggest that ovarian senescence can be delayed, potentially with health-extending results, if the processes that prevent uterine atrophy also prevent other health-related problems associated with female reproductive aging, such as bone loss and reduced cognition and cardiovascular function (see "More Than a Hot Flash").

Oxidative stress

Testicular testosterone biosynthesis. Testosterone (T) secretion declines slowly but steadily with age in men. A popular animal model to explore the biology underlying this observation is the Brown Norway (BN) rat. In the BN rat, serum T concentrations decline gradually with age, as does the maximal T secretion from isolated testicular Leydig cells exposed to exogenous luteinizing hormone (LH), which stimulates T production (10, 11). One interesting experiment led to the hypothesis that oxidative damage associated with T biosynthesis (a process that involves reactive oxygen generation as part of steroid biosynthetic mechanisms) may be responsible for the age-related decline in serum T. In this experiment, young (3 months) and middle-aged (13 months) BN rats were exposed to continuous doses of contraceptive levels of exogenous T for 8 months. This treatment sharply reduces LH secretion and effectively shuts down endogenous T production. Two months after removal of the T implant, the isolated Leydig cells of both groups (now 13 and 23 months of age) secreted "young" levels of T; in line with this result, the 23-month controls secreted significantly less T than those that had undergone this procedure (12), suggesting that the prevention of endogenous T biosynthesis serves to protect the steroid biosynthetic pathway from an age-related decline.

In testing this oxidative damage hypothesis to explain the age-related decline in serum T, these investigators report that mitochondria from old Leydig cells produce significantly greater levels of reactive oxygen species than do mitochondria from young cells (13). This finding is consistent with a more recent report from another laboratory with evidence that Leydig cell membrane preparations from old (24-month) Sprague-Dawley rats contain significantly more lipid peroxidation than do preparations from young (5-month) rats. The concentrations and activities of the antioxidant glutathione, as well as the concentrations of a variety of antioxidant enzymes at both the protein and the mRNA levels, were also lower in old versus young rats (14, 15). The association of greater oxidative damage in old rats with reduced T production is consistent with a later study in which exposure to the antioxidant vitamin E provided some protection from age-related changes in Leydig cell steroidogenesis (16). Taken together, these studies suggest that increasing oxidative damage with age may be at least partly responsible for declining T levels in older men, and that antioxidants may delay or prevent this decline to some extent.

Natriuretic response in the kidney. A recent Perspective in SAGE KE (17) (see Zheng Perspective) states that "renal disease is a much more common health problem than previously appreciated because nearly 3% of the U.S. population has elevated serum creatinine levels." Furthermore, even after subjects with clear sources of renal impairment (for example, diabetes and hypertension) were removed, 11% of those over 65 had renal function that was less than 60% of that in healthy younger people. This information along with information from studies that explored biological mechanisms of processes that reduced renal function with age was presented at the Biology of Aging Kidney workshop, held in January, 2003 and sponsored by NIA and NIDDK.

Renal aging is associated with structural and functional changes, such as declines in (i) renal blood flow, (ii) the filtration rate in the glomeruli (groups of capillaries in the kidney involved in blood filtration), and (iii) natriuretic and diuretic responses to the hormone dopamine, responses that cause the elimination of extra sodium in the urine and promote urination, respectively. Dopamine activates D1-like receptors (seven transmembrane domain receptors that exert their effects through G-protein signaling cascades) and inhibits the activity of the Na+/K+-ATPase (which transports sodium ions out of and potassium ions into the cell) in proximal tubules by protein kinase C (PKC) activation. This dopamine response is diminished in old rats as a result of the inability to inhibit Na+/K+-ATPase, due in part to D1 receptor G-protein uncoupling. This is caused by a higher basal PKC activity in old rats that causes membranous translocation of G-protein-coupled receptor kinase 2, which in turn phosphorylates the D1 receptor and uncouples it from G proteins (18-20). To test the hypothesis that increased age-related oxidative stress is responsible for the age-related diminished natriuretic response to dopamine, the Lokhandwala laboratory showed that markers of oxidant production and oxidative damage increased with age in renal proximal tubules (21). The association of oxidative damage with D1 receptor G-protein uncoupling, resulting in impairment of D1-like receptor function, was directly demonstrated using hydrogen peroxide treatment of primary cultures of rat renal proximal tubules (22). Furthermore, treatment of old rats with dietary antioxidants normalized the oxidative stress as well as the basal PKC activity in renal proximal tubules (23). Again, the concept is supported that age-related oxidative processes are associated with declining tissue function and that antioxidant treatment could at least partially reverse this damage.

Tissue Complexity as an Added Factor in Studies of Aging Physiology


Whether and how the many proposed aging-associated cell damage mechanisms affect tissue function are not simple questions to address, particularly considering the many different cell types and their interactions in tissues. For example, there are multiple cell types in bone. These include (i) bone-building cells, the osteoblasts; (ii) the osteocytes embedded within and responsible for maintaining the intercellular collagen matrix in bone tissue; (iii) the osteoclasts that destroy bone in the natural process of replacement and remodeling of bone; and (iv) the bone marrow, which has renewable sources for each of these cells as well as components for hematopoiesis (see "The Plot Thickens on Thin Bones"). These various differentiated cell types, and the marrow from which they are derived, are interdependent and, as well, influenced by factors from outside the bone, including biochemical factors from endocrine, nervous, and immune systems, and mechanical forces. Thus, to understand, predict, and possibly avoid detrimental health changes as we age, it is important to understand how particular cell types respond to aging-related damage, and how each response affects the tissue as a whole in light of the role of those cells within the tissue.

Although there is considerable evidence that cells in multiple tissues are aging in approximately the same time frame, it is also true that certain cells/tissues/systems seem to translate this aging into tissue dysfunction at earlier times or with greater regularity than others (see "Many Roads to Ruin"). Why this should be so is not yet known. For example, osteopenia (decreased bone density) is widespread with age. However, all bones within an individual are not affected to the same extent. An examination of the cellular events in bone has revealed an increase in apoptosis of osteoblasts with age, as a result of both the hormonal changes that accompany aging and additional aging mechanisms in both men and women. Research by the Manolagas laboratory on apoptosis in osteoblasts has shown that regulation of this process by estrogen receptor activation can stop and even reverse bone loss in mice (24). However, whether osteoblasts at different bone sites are differentially affected by aging, and whether regulation of cell death in other cell types within bone can help alleviate bone loss, are also active areas of investigation. Indeed, other regulators of apoptosis in both osteoclasts and osteoblasts can shift the balance of bone remodeling; some of these regulators are unexpected and can undergo important shifts with age, as shown in recent work on thyroid-stimulating factor and follicle-stimulating factor by Zaidi and colleagues (25, 26) (see "Bone Surprise").

Bisphosphonates, used as a major bone-saving treatment, act, at least in part, to inhibit apoptosis in a third type of bone cell, the osteocyte, as well as the osteoblast (27, 28). Thus, understanding how a prominent cellular feature of aging, increased apoptosis, can shift the balance of cell types within a tissue and lead to bone loss points the way toward treatments to alleviate the burden of osteoporosis in the elderly.

Skeletal muscle

Skeletal muscle is organized very differently from bone, but like bone it contains nerve, connective tissue, and vascular elements. Well-known changes in aging muscle involve loss in both mass and contractile force (29) [sarcopenia; see Hepple Perspective (2003)]. In addition, there is a loss of muscle repair function with age. The extent and effect of apoptosis or senescence in striated muscle nuclei, as representative of individual cells within the syncytium of the skeletal muscle fiber, is not clear; how apoptosis of some nuclei out of the many in a single fiber may result in muscle weakness and loss is also unclear (30). Further, the degree to which apoptosis increases in muscle nuclei with age varies with muscle type. Muscle fibers can be classified as type I or II depending on several cytological and contractile characteristics. The type II fiber-rich superficial vastus lateralis of the leg shows an age-linked increase in apoptosis, and the levels of apoptosis are influenced through the inflammatory modulator tumor necrosis factor-{alpha} (TNF{alpha}) (30, 31). Caloric restriction attenuates muscle fiber apoptosis and TNF{alpha} in rats (32). Not all muscles show this same response to aging, possibly because of different content of fiber types. In addition, the loss of force in muscle is at least partially related to loss of innervation (33). Innervation in aged muscle can be preserved by insulin-like growth factor-1 (IGF-1) at the muscle. IGF-1 delivered to the motor neuron can prevent the muscle fiber-specific loss of force (34) [see Hepple Perspective (2006)]. Furthermore, studies in mice show that physical forces can lead to muscle damage that is less readily repaired with age but can be mitigated by conditioning (35). Thus, locally produced growth factors, nervous input, and physical demands combine to affect the function of aging muscle. Much remains to be done to understand how oxidative stress and associated nucleic acid, protein, or lipid damage, or cell senescence or apoptosis exacerbate damage to the tissue within the context of this interactive system.


Both bone and skeletal muscle are tissues with a ready source of stem or progenitor cells to replace all of the parenchymal cell types (those cells essential for the specialized function of an organ or tissue); these include cells in the marrow for bone and the satellite cells in skeletal muscle. Thus, as cells die or function less well with age, some tissues have the potential for providing replacements. Cartilage is another tissue in which apoptosis increases with age (36), possibly as a result of increased susceptibility of the chondrocyte to oxidative stress of aging (37) (see Loeser Perspective). However, this tissue has a very limited capacity for repair through replacement of cells. Although progenitor cells have recently been reported in cartilage, and are seen in increased numbers in osteoarthritis (38), they often do not seem able to keep up with repair of the cartilage after damage or in aging. It may be that the physical isolation of cells in cartilage impinges on their ability to form replacement tissue, particularly at non-surface sites. Thus, this structural consideration may limit repair potential for this tissue.

Although on many levels, outcomes of aging may appear different in various systems because of differences in tissue structure and function, it seems likely that there are common mechanisms across tissues. For example, altered synthesis of extracellular matrix in cartilage could be expected to have effects on the integrity of the cartilage, leading to altered ability of the cartilage to respond appropriately to application of forces at the joint. However, altered synthesis of extracellular matrix in the bone marrow could be expected to alter the environment of critical stem cells for the hematopoietic and immune systems with quite different effects on overall health.

Mechanisms of tissue dysfunction

In recognition of the fact that the outcomes of common age-related changes may be disparate, BAP organized a series of workshops drawing together investigators who look at different tissues to discuss common underlying mechanisms of tissue dysfunction with age. These workshops included the Growth Hormone/IGF-1 and Aging Tissues Workshop in 2002, the Apoptosis and Aging Tissues Workshop in 2003, and a workshop titled "When do the Biological Changes of Aging Begin" in 2004 (see section below for further information on this workshop). This series of workshops not only brought investigators together to exchange research ideas and information but also highlighted a number of mechanisms and common themes across tissues. These themes include (i) recognition that the onset of aging-associated changes and functional deficits is seen in many tissues at early- to mid-adult life, (ii) the widespread involvement of inflammation and inflammatory cytokines in the aging phenotype (see Walston Perspective), (iii) the role of the aged microenvironment in cell function (including alterations to the extracellular matrix), and (iv) the potential for the balance between tissue turnover and regenerative capacity to play a major role in the emergence of the aged phenotype, often coincident with the formation of adipose tissue within or surrounding tissues. These themes were the subject of a presentation by BAP staff at an NIA retreat in 2003 and are reflected in several initiatives led or joined by BAP since. Two of these initiatives, The Adipogenic Phenotype in Aging Musculoskeletal Tissues, and Inflammation and Inflammatory Cytokines in Aging, have recently led to RFAs for support of investigations of declining function in tissues throughout the body.

As mentioned above, at a tissue and systems level the function and responses of individual tissues in aging are affected by changes in interacting tissues, as well as systemic changes. Recently, the Systems Branch of BAP has held workshops and begun initiatives to understand these broader interactions. This was the basis of the September 2004 workshop organized by several programs at NIA to understand the role of inflammation in aging pathology and health and led to an RFA (AG-05-011, "Inflammation, inflammatory mediators and aging") for research in this area. Discussions included not only how aging affects the immune system but also how changes to the immune system and the cytokines it produces can influence the health and function of other tissues, such as muscle. In November 2005, the immunology and endocrinology programs of BAP held a workshop on Endocrine-Immune Interactions in Aging. Presentations and discussion focused on a number of changes in both systems with age, how age-associated changes in one system affected the other, and how the altered function of aged endocrine and immune organs affects health. These types of workshops are enhancing discussion of systemic interactions affected by aging, likely to be an important emerging area of aging-related research.

Translation of Aging-Related Knowledge to Health Practice

One of the hopes of aging-related research is that understanding how cells change with age, and how the context of the cellular changes within the tissue helps explain altered tissue function, will lead to interventions to delay or mitigate age-related health declines. However, age-related changes and aging-related conditions are often studied with an emphasis on late life. As a result, there is comparatively little information on the initial stages of tissue decline. This is unfortunate, because interventions may not be as successful if applied in late life, after decades of damage and declining function have taken place. A key to translating our understanding of biological change with age into interventions may well be to support research on the early stages of aging-associated change in any given tissue. Evidence is clear that there are midlife and even early-adult age-related changes that occur in tissues and can be recognized, perhaps even before clinically important changes are evident. Because this theme recurred in multiple presentations of aging tissue research, BAP organized a workshop in 2004 called "When do the Biological Changes of Aging Begin?" The purpose was to examine research that clearly shows aging-related changes in many tissues in early- to mid-adult life and to provide a forum for discussion of how to approach the study of aging in midlife and young-adult tissues. As discussed at this workshop, such an area of study is not likely to be easy and may require new approaches. As populations age, variability in individual parameters often increases, making small but important differences harder to detect. Furthermore, tissues and organs have reserve and compensatory capabilities that may mask underlying biological changes caused by aging. Finally, we do not yet know exactly what to look for in the earliest steps related to aging-induced change. It is clear when a 90-year-old has suffered significant loss of muscle mass. Understanding when and how that loss was initiated and knowing what parameter(s) to measure at earlier ages is less clear. However, getting at the midlife roots of aging pathology may well be a promising component to translating the basic biology of aging to health practice.

Stem Cells As an Emerging Focus in Research on Aging Physiological Systems

The loss of cells or cell function through various cellular aging mechanisms must also be explained in the face of increasing evidence that replacement cells are available. The concept of stem cell and precursor cell availability in tissues is not a new one. The stem cells that are the basis of continual replacement of the gut epithelial lining have been known to exist for a long time, although they have only recently been more fully characterized. Skin is another tissue with recognized sources for cell replacement although, again, these cells have been more fully characterized in recent years [see, for example, (39)]. Bone marrow is a source of osteoblast precursors for bone building. Striated muscle has long been recognized to harbor muscle satellite cells that are the source of cells for fiber regeneration and hypertrophy. Additional sources of cells that can contribute to repair of damaged muscle have recently been characterized as well (40), and IGF-1 enhances their contribution (41). Even in systems in which stem cells had not previously been thought to renew parenchymal cells, a growing body of evidence indicates that stem cells may exist but not function adequately to maintain the tissue. For example, brain (42), heart (43), and even oocytes (44) may have sources of replacement cells where none had been known before. However, with dementias, heart failure, and menopause occurring as we age, the tissues involved in these diseases or conditions clearly are not being maintained and repaired optimally. The existence of these potential replacements for damaged parenchymal cells in tissues such as muscle and bone, in which aging leads to widespread limitations on activity and health, raises the question as to why such tissues are not fully maintained with age by stem and progenitor cells.

Understanding changes in stem cell biology that occur with age has been the focus of a major initiative within BAP and within NIA as a whole. Although a great deal of support has emerged for stem cell research through NIH and other organizations in recent years, BAP has approached this area with a particular focus on aging. Programmatic activities included RFAs in 2001 and again in 2004. In addition, programs in NIA have participated in multiple collaborative RFAs and PAs with other NIH institutes and centers to encourage growth of the research portfolio on stem cells in aging. Several questions in stem cell biology are of particular interest in the context of aging. In addition to understanding how tissues are maintained (or not) with age, research is needed to clearly understand (i) how and whether stem cells age (see Fuller Perspective), (ii) what the mechanisms are for retaining stem cell renewal throughout life, and (iii) what changes occur in the aging environment that may inhibit stem cell activation, division, and differentiation to maintain tissues. In turn, each of these questions has implications for the design and use of stem cell-based therapies in the elderly. BAP has continued to encourage discussion of stem cell research as it pertains to aging through leadership of an NIA Stem Cell Working Group, coordination of stem cell research support across NIH, and convening of multiple workshops for NIA stem cell research grantees (in 2003, 2004, and 2006). This effort has resulted in a portfolio of grants that is making important contributions to understanding tissue pathology and tissue repair. Results of NIA-supported work presented at the most recent grantee meeting (Stem Cells and Aging, 2006, Bethesda, MD) and in the literature show that there are changes to some stem cells with age, but that the aged environment is a major factor in stem cell biology. For example, mouse parabiosis experiments (which involve linking the circulatory systems of two animals) show that the aged environment plays a crucial role in inhibition of muscle regeneration (45) (see "Buddy System"). The mouse immune system, if given a chance, can generate new T cells from existing stem cell pools in the thymus of aged animals, and these cells have characteristics of younger, more effective cells (46). However, the stem cells themselves may impose an aged phenotype in tissues. Aging of mesangial stem cells may contribute to renal glomerular aging (the mesangium is a region of the glomerulus between capillaries). A recent study from the Striker laboratory (47) explored the role of mesangial stem or progenitor cell aging in age-related glomerulosclerosis (scarring of the glomerulus) in mice. They observed that "postmenopausal" females and age-matched males show progressive glomerular hypertrophy and glomerulosclerosis. In the process of doing bone marrow transplants (BMT) between young and old females, they found that BMT produced a glomerular phenotype that was donor age-specific: Young animals had a hypertrophic, sclerotic phenotype when the BMT donor was an old female, and old animals with young BMT showed a diminution of their hypertrophic, sclerotic phenotype. This fascinating result suggests that mesangial stem cells, presumably localized in bone marrow, largely determine the renal glomerular phenotype, and that the source of the hypertrophic, sclerotic phenotype in aging is, at least in part, attributable to mesangial stem cell aging.

Summary and Conclusions

Research to understand how aging results in tissue pathology and dysfunction is still a relatively new area, yet it is already paying dividends. Potential directions have been uncovered for the alleviation of conditions that take a toll on the health and quality of life for older adults, conditions such as osteopenia, sarcopenia, increased susceptibility to infection, and decreased hormone production. The continued application of knowledge of cellular processes of aging in the context of the physical and biochemical milieu of tissues composed of multiple cell types--and a better understanding of early changes that lead to tissue dysfunction at older ages--will likely aid in developing interventions to improve health. Progress thus far points to the importance of broadening our view of aging tissues to encompass interacting systems as well as multiple cell types and roles. Development of interventions to lessen suffering and lengthen healthy life span as we age will likely entail approaches to mitigate degenerative processes at earlier stages of aging than we are currently focused on.

June 28, 2006
  1. H. R. Warner, Developing a research agenda in biogerontology: Basic mechanisms. Sci. Aging Knowledge Environ. 2005(44), pe33 (2005).
  2. T. R. Brown, C. Lee, Conference summary on prostate growth and aging, 13-15 September 2000. Prostate 48, 54-65 (2001).[CrossRef][Medline]
  3. J. Choi, I. Shendrik, M. Peacocke, D. Peehl, R. Buttyan, E. F. Ikeguchi, A. E. Katz, M. C. Benson, Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. Urology 56, 160-166 (2000).[CrossRef][Medline]
  4. P. Castro, D. Giri, D. Lamb, M. Ittmann, Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 55, 30-38 (2003).[CrossRef][Medline]
  5. P. Castro, D. Giri, D. Lamb, M. Ittmann, Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 55, 30-38 (2003).[CrossRef][Medline]
  6. C. Sandhu, D. M. Peehl, J. Slingerland, p16INK4A mediates cyclin dependent kinase 4 and 6 inhibition in senescent prostatic epithelial cells. Cancer Res. 60, 2616-2622 (2000).[Abstract/Free Full Text]
  7. S. R. Schwarze, Y. Shi, V. X. Fu, P. A. Watson, D. F. Jarrard, Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene 20, 8184-8192 (2001).[CrossRef][Medline]
  8. B. Bhatia, S. Tang, P. Yang, A. Doll, G. Aumueller, R. A. Newman, D. G. Tang, Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells. Oncogene 24, 3583-3595 (2005).[CrossRef][Medline]
  9. G. I. Perez, R. Robles, C. M. Knudson, J. A. Flaws, S. J. Korsmeyer, J. L. Tilly, Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat. Genet. 21, 200-203 (1999).[CrossRef][Medline]
  10. B. R. Zirkin, R. Santulli, J. D. Strandberg, W. W. Wright, L. L. Ewing, Testicular steroidogenesis in the aging brown Norway rat. J. Androl. 14, 118-123 (1993).[Medline]
  11. H. Chen, M. P. Hardy, I. Huhtaniemi, B. R. Zirkin, Age-related decreased Leydig cell testosterone production in the brown Norway rat. J. Androl. 15, 551-557 (1994).[Medline]
  12. H. Chen, B. R. Zirkin, Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging. Proc. Natl. Acad. Sci. U.S.A. 96, 14877-14881 (1999).[Abstract/Free Full Text]
  13. H. Chen, D. Cangello, S. Benson, J. Folmer, H. Zhu, M. A. Trush, B. R. Zirkin, Age-related increase in mitochondrial superoxide generation in the testosterone-producing cells of Brown Norway rat testes: relationship to reduced steroidogenic function? Exp. Gerontol. 36, 1361-1373 (2001).[CrossRef][Medline]
  14. L. Cao, S. Leers-Sucheta, S. Azhar, Aging alters the functional expression of enzymatic and non-enzymatic anti-oxidant defense systems in testicular rat Leydig cells. J. Steroid Biochem. Mol. Biol. 88, 61-67 (2004).[CrossRef][Medline]
  15. L. Luo, H. Chen, M. A. Trush, M. D. Show, M. D. Anway, B. R. Zirkin, Aging and the brown Norway rat Leydig cell antioxidant defense system. J. Androl. 27, 240-247 (2006).[CrossRef][Medline]
  16. H. Chen, J. Liu, L. Luo, M. U. Baig, J. M. Kim, B. R. Zirkin, Vitamin E, aging and Leydig cell steroidogenesis. Exp. Gerontol. 40, 728-736 (2005).[CrossRef][Medline]
  17. F. Zheng, A. R. Plati, A. Banerjee, S. Elliot, L. J. Striker, G. E. Striker, The molecular basis of age-related kidney disease. Sci. Aging Knowledge Environ. 2003(29), pe20 (2003).
  18. V. Kansra, T. Hussain, M. F. Lokhandwala, Alterations in dopamine DA1 receptor and G proteins in renal proximal tubules of old rats. Am. J. Physiol. 273, F53-F59 (1997).
  19. S. Beheray, V. Kansra, T. Hussain, M .F. Lokhandwala, Diminished natriuretic response to dopamine in old rats is due to an impaired D1-like receptor-signaling pathway. Kidney Int. 58, 712-720 (2000).[CrossRef][Medline]
  20. M. Asghar, V. Kansra, T. Hussain, M. F. Lokhandwala, Hyperphosphorylation of Na-pump contributes to defective renal dopamine response in old rats. J. Am. Soc. Nephrol. 12, 226-232 (2001).[Abstract/Free Full Text]
  21. M. Asghar, M. F. Lokhandwala, Antioxidant supplementation normalizes elevated protein kinase C activity in the proximal tubules of old rats. Exp. Biol. Med. (Maywood) 229, 270-275 (2004).[Abstract/Free Full Text]
  22. M. Asghar, A. A. Banday, R. Z. Fardoun, M. F. Lokhandwala, Hydrogen peroxide causes uncoupling of dopamine D1-like receptors from G proteins via a mechanism involving protein kinase C and G-protein-coupled receptor kinase 2. Free Radic. Biol. Med. 40, 13-20 (2006).[CrossRef][Medline]
  23. M. Asghar, M. F. Lokhandwala, Antioxidant supplementation normalizes elevated protein kinase C activity in the proximal tubules of old rats. Exp. Biol. Med. (Maywood) 229, 270-275 (2004).[Abstract/Free Full Text]
  24. S. Kousteni, J. R. Chen, T. Bellido, L. Han, A. A. Ali, C. A. O'Brien, L. Plotkin, Q. Fu, A. T. Mancino, Y. Wen et al., Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298, 843-846 (2002).[Abstract/Free Full Text]
  25. E. Abe, R. C. Marians, W. Yu, X. B. Wu, T. Ando, Y. Li, J. Iqbal, L. Eldeiry, G. Rajendren, H. C. Blair et al., TSH is a negative regulator of skeletal remodeling. Cell 115, 151-162 (2003).[CrossRef][Medline]
  26. L. Sun, Y. Peng, A. C. Sharrow, J. Iqbal, Z. Zhang, D. J. Papachristou, S. Zaidi, L. L. Zhu, B. B. Yaroslavskiy, H. Zhou et al., FSH directly regulates bone mass. Cell 125, 247-260 (2006).[CrossRef][Medline]
  27. L .I. Plotkin, R. S. Weinstein, A. M. Parfitt, P. K. Roberson, S. C. Manolagas, T. Bellido, Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J. Clin. Invest. 104, 1363-1374 (1999).[CrossRef][Medline]
  28. L. I. Plotkin, J. I. Aguirre, S. Kousteni, S. C. Manolagas, T. Bellido, Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J. Biol. Chem. 280, 7317-7325 (2005).[Abstract/Free Full Text]
  29. J. A. Faulkner, S. V. Brooks, E. Zerba, Muscle atrophy and weakness with aging: Contraction-induced injury as an underlying mechanism. J. Gerontol. A Biol. Sci. Med. Sci. 50 Spec. No., 124-129 (1995).
  30. A. J. Dirks, C. Leeuwenburgh, The role of apoptosis in age-related skeletal muscle atrophy. Sports Med. 35, 473-483 (2005).[CrossRef][Medline]
  31. A. J. Dirks, C. Leeuwenburgh, Tumor necrosis factor alpha signaling in skeletal muscle: effects of age and caloric restriction. J. Nutr. Biochem. 1 December 2005 [e-pub ahead of print]. doi:10.1016/j.jnutbio.2005.11.002
  32. T. Phillips, C. Leeuwenburgh, Muscle fiber specific apoptosis and TNF-alpha signaling in sarcopenia are attenuated by life-long calorie restriction. FASEB J. 19, 668-670 (2005).[Abstract/Free Full Text]
  33. Z. M. Wang, Z. Zheng, M. L. Messi, O. Delbono, Extension and magnitude of denervation in skeletal muscle from ageing mice. J. Physiol. 565, 757-764 (2005).[CrossRef][Medline]
  34. A. M. Payne, Z. Zheng, M. L. Messi, C. E. Milligan, E. Gonzalez, O. Delbono, Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle. J. Physiol. 570, 283-294 (2006).[CrossRef][Medline]
  35. S. V. Brooks, J. A. Opiteck, J. A. Faulkner, Conditioning of skeletal muscles in adult and old mice for protection from contraction-induced injury. J. Gerontol. A Biol. Sci. Med. Sci. 56, B163-B171 (2001).[Abstract/Free Full Text]
  36. C. S. Adams, W. E. Horton Jr., Chondrocyte apoptosis increases with age in the articular cartilage of adult animals. Anat. Rec. 250, 418-425 (1998).[CrossRef][Medline]
  37. M. D. Carlo Jr., R. F. Loeser, Increased oxidative stress with aging reduces chondrocyte survival: Correlation with intracellular glutathione levels. Arthritis Rheum. 48, 3419-3430 (2003).[CrossRef][Medline]
  38. S. Alsalameh, R. Amin, T. Gemba, M. Lotz, Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 50, 1522-1532 (2004).[CrossRef][Medline]
  39. J. R. Bickenbach, K. L. Grinnell, Epidermal stem cells: Interactions in developmental environments. Differentiation 72, 371-380 (2004).[CrossRef][Medline]
  40. A. T. Palermo, M. A. LaBarge, R. Doyonnas, J. Pomerantz, H. M. Blau, Bone marrow contribution to skeletal muscle: A physiological response to stress. Dev. Biol. 279, 336-344 (2005).[CrossRef][Medline]
  41. A. Sacco, R. Doyonnas, M. A. LaBarge, M. M. Hammer, P. Kraft, H. M. Blau, IGF-I increases bone marrow contribution to adult skeletal muscle and enhances the fusion of myelomonocytic precursors. J. Cell Biol. 171, 483-492 (2005).[Abstract/Free Full Text]
  42. G. Kempermann, H. G. Kuhn, J. Winkler, F. H. Gage, New nerve cells for the adult brain. Adult neurogenesis and stem cell concepts in neurologic research. Nervenarzt. 69, 851-857 (1998).[CrossRef][Medline]
  43. A. Linke, P. Muller, D. Nurzynska, C. Casarsa, D. Torella, A. Nascimbene, C. Castaldo, S. Cascapera, M. Bohm, F. Quaini et al., Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc. Natl. Acad. Sci. U.S.A. 102, 8966-8971 (2005).[Abstract/Free Full Text]
  44. J. Johnson, J. Canning, T. Kaneko, J. K. Pru, J. L. Tilly, Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145-150 (2004).[CrossRef][Medline]
  45. I. M. Conboy, M. J. Conboy, A. J. Wagers, E. R. Girma, I. L. Weissman, T. A. Rando, Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760-764 (2005).[CrossRef][Medline]
  46. L. Haynes, S. M. Eaton, E. M. Burns, T. D. Randall, S. L. Swain, Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen. J. Exp. Med. 201, 845-851 (2005).[Abstract/Free Full Text]
  47. Z. Feng, A. R. Plati, Q. L. Cheng, M. Berho, A. Banerjee, M. Potier, W. C. Jy, A. Koff, L. J. Striker, G. E. Striker, Glomerular aging in females is a multi-stage reversible process mediated by phenotypic changes in progenitors. Am. J. Pathol. 167, 355-363 (2005).[Medline]
Citation: J. L. Carrington, F. L. Bellino, Developing a Research Agenda in Biogerontology: Physiological Systems. Sci. Aging Knowl. Environ. 2006 (10), pe17 (2006).

Science of Aging Knowledge Environment. ISSN 1539-6150