eBriefing

Disease Drivers of Aging: The 2016 Advances in Geroscience Summit

Disease Drivers of Aging
Reported by
Jennifer Cable

Posted July 06, 2016

Presented By

Gerontological Society of America

American Federation for Aging Research

Trans-NIH GeroScience Interest Group

The New York Academy of Sciences

Overview

The processes associated with aging may be risk factors for age-related diseases. Conversely, many age-related chronic diseases accelerate aging. However, because most research is focused on specific diseases, the broad mechanisms of disease as a driver of aging have not been well studied. Understanding how disease drives aging could not only help people live longer but also improve health and quality of life during old age.

On April 13–14, 2016, researchers studying aging and three disease areas—HIV/AIDS, oncology, and diabetes—met at the New York Academy of Sciences for the Disease Drivers in Aging: 2016 Advances in Geroscience Summit. The meeting expanded on the National Institutes of Health's 2013 Advances in Geroscience Summit, examining how chronic diseases and their treatments affect aging. The meeting also aimed to stimulate collaboration between researchers studying aging and researchers studying disease. The summit was presented by the Gerontological Society of America, the American Federation for Aging Research, the Trans-NIH GeroScience Interest Group, and the New York Academy of Sciences.

The meeting opened with four keynote presentations from geroscience researchers, followed by a series of short talks and panel discussions featuring researchers focused on HIV/AIDS, diabetes, and cancer. This eBriefing reviews the panel discussions on each disease area and the overarching discussion on common themes and ideas for collaboration between researchers studying aging and disease.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Timothy Ahles, PhD (Memorial Sloan Kettering Cancer Center)
Kathryn Anastos, MD (Albert Einstein College of Medicine)
Steven Austad, PhD (University of Alabama at Birmingham)
James Becker, PhD (University of Pittsburgh)
Caroline Blaum, MD (New York University)
Judith Campisi, PhD (Buck Institute for Research on Aging)
Harvey J. Cohen, MD (Duke University)
Wendy Demark-Wahnefried, PhD (University of Alabama at Birmingham)
Jan van Deursen, PhD (Mayo Clinic)
Elissa Epel, MD (University of California, San Francisco)
Kristine Erlandson, MD (University of Colorado)
Brooke Grindlinger, PhD (The New York Academy of Sciences)
Jeffrey Halter, MD (University of Michigan)
Richard Hodes, MD (National Institute on Aging, NIH)
Peter Hunt, MD (University of California, San Francisco)
Beth Jamieson, PhD (University of California, Los Angeles)
C. Ronald Kahn, MD (Joslin Diabetes Center)
Balakuntalam Kasinath, MD (University of Texas Health Science Center)
Gretchen Neigh, PhD (Virginia Commonwealth University)
Rosario Scalia, MD, PhD (Temple University)
Marissa Schafer, PhD (Robert and Arlene Kogod Center on Aging)
Felipe Sierra, PhD (National Institute on Aging, NIH)
Mary Sehl, MD, PhD (University of California, Los Angeles)
Christopher Wiley, PhD (Buck Institute for Research on Aging)
Panel Discussions


Presented by

  • The Gerontological Society of America
  • The New York Academy of Sciences

How to cite this eBriefing

The New York Academy of Sciences. Disease Drivers of Aging: The 2016 Advances in Geroscience Summit. Academy eBriefings. 2016. Available at: www.nyas.org/Geroscience2016-eB

The Geroscience Hypothesis: What Do We Know?


Steven Austad (University of Alabama at Birmingham)
  • 00:01
    1. Introduction and overview
  • 04:25
    2. What we know from basic research
  • 11:58
    3. Progress made; What we want to know; Conclusio

Physiological Stress, Chronic Diseases, and Telomere Length


Elissa Epel (University of California, San Francisco)
  • 00:01
    1. Introduction and overview
  • 08:20
    2. Chronic stress and cell aging
  • 13:04
    3. Telomeres and disease risk
  • 15:55
    4. Disease drivers; Conclusion

1: Aging with HIV — Responding to an Emerging Challenge


Beth Jamieson (UCLA), James Becker (University of Pittsburgh), and Gretchen Neigh (Virginia Commonwealth University)
  • 00:01
    1. Presentation by Beth Jamieson
  • 10:20
    2. Presentation by James Becker
  • 19:52
    3. Presentation by Gretchen Neig

2: Aging with HIV — Responding to an Emerging Challenge


Kathryn Anastos (Albert Einstein College of Medicine), Peter Hunt (UCSF), and Kristine Erlandson (University of Colorado)
  • 00:01
    1. Presentation by Kathryn Anastos
  • 10:16
    2. Presentaton by Peter Hunt
  • 20:23
    3. Presentation by Kristine Erlandso

Session II Panel Discussion


  • 00:01
    1. Introduction; HIV and aging
  • 08:25
    2. HIV and macrophages; Primate studies; Where to intervene
  • 16:21
    3. Maximizing control group resources; Biomarkers for stress
  • 23:48
    4. Regarding Alzheimer's; Mitochondrial dysfunction; Aging and viral dormancy; Data set creation
  • 28:56
    5. Supressor mutations; Cognitive dysfunction; Conclusio

Emerging Science — Hot Topic Talks


Marissa Schafer (Robert and Arlene Kogod Center on Aging), Christopher Wiley (Buck Institute for Research on Aging), and Mary Sehl (UCLA)
  • 00:01
    1. Presentation by Marissa Schafer
  • 11:07
    2. Presentation by Christopher Wiley
  • 22:09
    3. Presentaton by Mary Seh

1: Examining the Impacts of Diabetes on Aging


C. Ronald Kahn (Joslin Diabetes Center), Rosario Scalia (Temple University), and Balakuntalam Kasinath (University of Texas Health Science Center)
  • 00:01
    1. Presentation by C. Ronald Kahn
  • 10:29
    2. Presentation by Balakuntalam Kasinath
  • 20:47
    3. Presentation by Rosario Scali

2: Examining the Impacts of Diabetes on Aging


Caroline Blaum (NYU) and Jeffrey Halter (University of Michigan)
  • 00:01
    1. Presentation by Caroline Blaum
  • 10:35
    2. Presentation by Jeffrey Halte

Session IV Panel Discussion


  • 00:01
    1. Treatment with CDK4 inhibitors; What is accelerated aging?
  • 09:03
    2. Increased phosphorylation; Obesity, asthma, and diabetes
  • 13:55
    3. Amino acids and insulin secretion; More on accelerated aging
  • 18:52
    4. Regarding astroglial cells; The blood-brain barrier
  • 26:40
    5. Treatment with metformin; Diabetes and immunodeficiency; Rapamycin; Conclusio

Editor's Guide to Writing and Publishing Your Paper


Brooke Grindlinger (The New York Academy of Sciences)
  • 00:01
    1. Introduction; Choosing the right journal
  • 04:20
    2. General manuscript preparation; Discussion and introduction
  • 11:44
    3. The abstract; The title
  • 14:38
    4. Authorship; The cover letter
  • 21:44
    5. Referees; Peer review
  • 27:44
    6. Decisions; Common reasons for rejection; Revision and resubmission
  • 34:35
    7. Preparing a response; Appealing a negative decision
  • 39:12
    8. Parting thoughts; Conclusio

1: Understanding and Mitigating Premature Aging Due To Cancer and Chemotherapy


Jan van Deursen (Mayo Clinic), Harvey J. Cohen (Duke University), and Judith Campisi (Buck Institute for Research on Aging)
  • 00:01
    1. Presentation by Jan van Deursen
  • 11:48
    2. Presentation by Harvey Jay Cohen
  • 22:09
    3. Presentation by Judith Campis

2: Understanding and Mitigating Premature Aging Due To Cancer and Chemotherapy


Wendy Demark-Wahnefried (University of Alabama at Birmingham) and Timothy Ahles (Memorial Sloan Kettering Cancer Center)
  • 00:01
    1. Presentation by Wendy Denmark-Wahnefried
  • 10:29
    2. Presentation by Timothy Ahle

Session V Panel Discussion


  • 00:01
    1. Introduction
  • 07:48
    2. Synergy between aging and cancer research models; Aging in animal models
  • 17:30
    3. Disease interplay across disciplines; Dietary restriction; Senescent T-cells
  • 24:12
    4. Computational and systems biology; Chemotherapy and senescence; Funding
  • 31:11
    5. Anti-depressants before chemo; Intervention
  • 40:15
    6. Regarding exosomes and evolution; Conclusio

Session VI Panel Discussion


Moderator: Felipe Sierra (National Institute on Aging, NIH)
  • 00:01
    1. Panelists' opening remarks
  • 13:17
    2. Disease treatment and lifespan extension; Targeting senescenct cells
  • 21:06
    3. Embracing complexity; Developmental manipulation in aging research; Inflammation
  • 33:20
    4. Review and funding
  • 41:00
    5. Metabolic reprogramming; Healthspan vs. lifespan; Regarding data sets
  • 48:18
    6. Mitochondrial dysfunction; Going forward; Common tools
  • 61:28
    7. Aging as disease; Stress and trauma; Drug discovery; Influence of local environment
  • 69:28
    8. Exercise; Incentivizing collaboration; Policy and funding
  • 82:06
    9. Focus on gene expression; Big data; Public perceptions
  • 87:27
    10. Cohort development; Conclusio

Geroscience as a Multidisciplinary Approach to Understanding Aging


Richard Hodes (National Institute on Aging, NIH)

Disease Drivers of Aging as a Topic for Geroscience


Felipe Sierra (National Institute on Aging, NIH)

Resources

General aging resources: websites

Frontiers in Geroscience. J Gerontol. 2014;69 Suppl 1
Supplemental issue of the Journals of Gerontology containing articles related to the first Geroscience Summit.

NIH Geroscience Interest Group
Trans-NIH organization to raise awareness of the role of aging in disease.

Sierra F, Kohanski R (eds). Advances in Geroscience. Springer International Publishing. 2016. [Ebook]
Provides a comprehensive overview of geroscience.

General aging resources: journal articles

National Institute on Aging (NIA)
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life.

Bansal A, Zhu LF, Yen K, Tissenbaum HA. Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci U S A. 2015;112:E277-E286.

Kennedy BK, Berger SL, Brunet A, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159:709-713.

Lopez-Otin C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell. 2013;153:1192-1217.

Lunney JR, Lynn J, Foley DJ, et al. Patterns of functional decline at end of life. JAMA. 2003;289:2387-2392.

St Sauver JL, Boyd CM, Grossardt BR, et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open. 2015;5:e006413.

Research and funding opportunities: websites

Impact of Aging on Currently Employed Animal Models of Disease and Chronic Conditions
Recent NIA request for applications.

NIA Interventions Testing Program
Multi-site study that investigates the potential for treatments to extend life span and delay dysfunction in mice.

HIV and aging resources: journal articles

Becker JT, Lopez OL, Dew MA, Aizenstein HJ. Prevalence of cognitive disorders differs as a function of age in HIV virus infection. AIDS. 2004;18 Suppl 1:S11-S8.

Cohen MH, Hotton AL, Hershow RC, et al. Gender-related risk factors improve mortality predictive ability of VACS Index among HIV-infected women. J Acquir Immune Defic Syndr. 2015;70:538-544.

Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during chronic HIV infection. Immunity. 2013;39:633-645.

Lee SA, Sinclair E, Hatano H, et al. Impact of HIV on CD8+ T cell CD57 expression is distinct from that of CMV and aging. PLoS One. 2014;9:e89444.

Rickabaugh TM, Baxter RM, Sehl M, et al. Acceleration of age-associated methylation patterns in HIV-1-infected adults. PLoS One. 2015;10:e0119201.

Schrack JA, Althoff KN, Jacobson LP, et al. Accelerated longitudinal gait speed decline in HIV-infected older men. J Acquir Immune Defic Syndr. 2015;70:370-376.

Diabetes and aging resources: journal articles

Chang AM, Smith MJ, Galecki AT, et al. Impaired beta-cell function in human aging: response to nicotinic acid-induced insulin resistance. J Clin Endocrinol Metab. 2006;91:3303-3309.

Cheng Z, Jiang X, Pansuria M, et al. Hyperhomocysteinemia and hyperglycemia induce and potentiate endothelial dysfunction via µ-calpain activation. Diabetes. 2015;64:947-959.

Han BH, Blaum CS, Ferris RE, et al. Older adults reporting more diabetes mellitus care have greater 9-year survival. J Am Geriatr Soc. 2015;63:2455-2462.

Kleinridders A, Cai W, Cappellucci L, et al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci U S A. 2015;112:3463-3468.

Mariappan MM, Prasad S, D'Silva K, et al. Activation of glycogen synthase kinase 3β ameliorates diabetes-induced kidney injury. J Biol Chem. 2014;289:53563-35375.

Cancer and aging resources: journal articles

Bouchlaka MN, Sckisel GD, Chen M, et al. Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med. 2013;210:2223-2237.

Dale W, Mohile SG, Eldadah BA, et al. Biological, clinical, and psychosocial correlates at the interface of cancer and aging research. J Natl Cancer Inst. 2012;104:581-589.

Lecot P, Alimirah R, Desprez PY, et al. Context-dependent effects of cellular senescence in cancer development. Br J Cancer. 2016. [Epub]

Mandelblatt JS, Jacobsen PB, Ahles T. Cognitive effects of cancer systemic therapy: implications for the care of older patients and survivors. J Clin Oncol. 2014;32:2617-2626.

Mohile SG, Hurria A, Cohen HJ, et al. Improving the quality of survivorship for older adults with cancer. Cancer. 2016.

Van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439-446.

Organizers

James Appleby, RPh, MPH

The Gerontological Society of America
website

Steven Austad, PhD

University of Alabama at Birmingham
website | publications

Rita Effros, PhD

University of California, Los Angeles
website | publications

Rebecca Fuldner, PhD

National Institute on Aging, NIH
website | publications

Paige Green, PhD, MPH

National Cancer Institute, NIH
website | publications

Robin Huebner, PhD, MPH

National Institute of Allergy and Infectious Diseases, NIH

Ronald Kohanski, PhD

National Institute on Aging, NIH
website | publications

Stephanie Lederman, EdM

American Federation for Aging Research
website | publications

Kevin J. Lee, PhD

The Lawrence Ellison Foundation; American Federation for Aging Research
website

Judie Lieu

The Gerontological Society of America
website

Francesca Macchiarini, PhD

National Institute of Allergy and Infectious Diseases, NIH
website | publications

Susan McCarthy, PhD

National Cancer Institute, NIH
website | publications

Aaron Pawlyk, PhD

National Institute of Diabetes and Digestive and Kidney Diseases, NIH
website | publications

Felipe Sierra, PhD

National Institute on Aging, NIH
website | publications

Luke Stoeckel, PhD

National Institute of Diabetes and Digestive and Kidney Diseases, NIH
website | publications

Odette van der Willik

American Federation for Aging Research
website | publications

Siobhan Addie, PhD

Formerly at the New York Academy of Sciences

Brooke Grindlinger, PhD

The New York Academy of Sciences


Speakers

Timothy Ahles, MD

Memorial Sloan Kettering Cancer Center
website | publications

Kathryn Anastos, MD

Albert Einstein College of Medicine
website | publications

Nir Barzilai, MD

Albert Einstein College of Medicine
website | publications

James Becker, PhD

University of Pittsburgh
website | publications

Caroline Blaum, MD

New York University
website | publications

Judith Campisi, PhD

Buck Institute for Research on Aging
website | publications

Harvey J. Cohen, MD

Duke University
website | publications

Steven Deeks, MD

AIDS Research Institute; University of California, San Francisco
website | publications

Wendy Demark-Wahnefried, PhD, RD

University of Alabama at Birmingham
website | publications

Jan van Deursen, PhD

Mayo Clinic
website | publications

Elissa Epel, MD

University of California, San Francisco
website | publications

Kristine Erlandson, MD

University of Colorado
website | publications

Claudia Gravekamp, PhD

Albert Einstein College of Medicine
website | publications

Jeffrey Halter, MD

University of Michigan
website | publications

Kevin High, MD

Wake Forest University
website | publications

Richard Hodes, MD

National Institute on Aging, National Institutes of Health
website | publications

Peter Hunt, MD

University of California, San Francisco
website | publications

Arti Hurria, MD

City of Hope National Medical Center
website | publications

Beth Jamieson, PhD

University of California, Los Angeles
website | publications

C. Ronald Kahn, PhD

Joslin Diabetes Center
website | publications

Balakuntalam Kasinath, MD

University of Texas Health Science Center
website | publications

Gretchen Neigh, PhD

Virginia Commonwealth University
website | publications

Marissa Schafer, PhD

Mayo Clinic College of Medicine
publications

Rosario Scalia, MD, PhD

Temple University
website | publications


Jennifer Cable

Jennifer Cable lives in New York City, where she experiments with different outlets to communicate science. She enjoys bringing science to scientists and nonscientists alike. She writes for Nature Structural and Molecular Biology, Bitesize Bio, Under the Microscope, and the Nature New York blog. She received a PhD from the University of North Carolina at Chapel Hill for her research in investigating the structure/function relationship of proteins.

Sponsors

Silver Sponsor

Academy Friends

Alliance for Aging Research

American Federation for Aging Research

American Geriatrics Society

The Gerontological Society of America

Novartis

Grant Support

Funding for the eBriefing of this conference was made possible, in part, by 1 R13 AG 053043-01 from the National Institute on Aging. Co-funding has been provided by the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Cancer Institute. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com

Gilead Sciences, Inc.

Regeneron Pharmaceuticals, Inc.


Presented by

  • The Gerontological Society of America
  • The New York Academy of Sciences

Keynote Speakers

Richard Hodes

National Institute on Aging, NIH

Felipe Sierra

National Institute on Aging, NIH

Steven Austad

University of Alabama at Birmingham

Elissa Epel

University of California, San Francisco

Highlights

Although age is an important variable in clinical research, the effects of aging are often understudied.

Improving the quality of life during aging is as important as increasing longevity.

Short-term stress can promote resilience to aging; however, chronic stress accelerates aging.

Introduction

Aging is often accompanied by chronic diseases including heart disease, cancer, diabetes, and Alzheimer's disease, to name a few. Many processes associated with aging may be risk factors for these diseases. While aging occurs in the absence of disease—a steady decline in health is expected as a person ages—chronic diseases also accelerate aging, exacerbating normal physical and cognitive decline.

As people age, a steady decline in health is expected (red line). Some diseases cause a temporary decrease in health followed by full recovery (first black dip). However, other diseases can change the trajectory of aging, leading to a faster decline in health (fuchsia line). (Image courtesy of Felipe Sierra)

The field of geroscience has focused on how aging affects disease, and this topic was the theme of the first geroscience summit, "Advances in Geroscience: Impact on Healthspan and Chronic Disease," which took place in October, 2013, in Bethesda, Maryland. Papers related to that summit were published in a supplement to the Journals of Gerontology in June, 2014. However, the reverse question—how disease affects aging—has gone largely unstudied, and this topic was the theme of this 2016 meeting.

The 2016 summit examined how three diseases—HIV/AIDS, diabetes, and cancer—affect the major pillars of aging established at the first Geroscience Summit: macromolecular damage, stress response, epigenetics, stem cells, proteostasis, inflammation, and metabolism.

The meeting opened with four keynote presentations from geroscience researchers who described successful interventions to delay aging and increase life span in animal models. They also noted the need for multidisciplinary research, challenging attendees to work across disease states. Understanding common mechanisms in aging and chronic diseases could help people live not only longer but also healthier lives.The keynote presentations were followed by a series of short talks and panel discussions featuring researchers focused on HIV/AIDS, diabetes, and cancer. This eBriefing reviews the panel discussions on each disease area and the overarching discussion on common themes and ideas for collaboration between researchers studying aging and disease.

The seven pillars of aging. (Image: Kennedy BK et al., Cell 159: 709-713 [2014])

A multidisciplinary approach to aging

Richard Hodes of the National Institute of Aging (NIA) outlined the multidisciplinary structure at the NIA and National Institutes of Health (NIH) to raise awareness of the role of aging in disease and to fund aging-based research. Targeting aging may reduce the incidence of age-related diseases. The divisions of the NIA span basic biology to clinical and behavioral studies. Because aging touches so many fields, the NIH also created the Geroscience Interest Group (GSIG), with members from 21 institutes. Hodes called on researchers to step outside the silos of their specialties and to study features of aging common to disparate disciplines and diseases.

Hodes also presented evidence of the importance of considering age when choosing treatments for patients, and highlighted the need to include elderly subjects in preclinical and clinical studies. In the Diabetes Prevention Program, both medication and lifestyle changes reduced the risk of developing diabetes in at-risk patients younger than 60 years. However, in subjects older than 60, only lifestyle changes were effective. In a pre-clinical study, elderly mice with cancer died sooner when given immunotherapy than those who did not receive treatment.

Felipe Sierra, also from the NIA, pointed to the need to re-examine our approach to disease. The elderly often present with several comorbidities. Instead of considering each disease individually, researchers should consider interactions between diseases, and between disease and aging.

The keynote speakers also described efforts to promote aging research. In late 2015, the NIA released a request for applications to test whether the age of laboratory animals affects outcomes in studies investigating disease. In the NIA's Interventions Testing Program (ITP), researchers can submit compounds to be tested for an effect on extending life span in mice.

Increasing health span as well as life span

Steven Austad of the University of Alabama at Birmingham emphasized that increasing longevity is not the same as improving health. Several interventions can extend life span in animals. In some cases, such as the use of rapamycin in mice, health span is also improved. Indeed, rapamycin extends life and delays Alzheimer's disease, cancer, atherosclerosis, and heart dysfunction in mice. However, genetic mutations that increase life span in the worm Caenorhabditis elegans do not extend the period of good health. Furthermore, life-extending interventions are not without side effects. In mice, dietary restriction and rapamycin have been linked to low bone density, immunosuppression, cataracts, diabetes, and hyperlipidemia.

Life expectancy (gray) and health expectancy (blue) of men and women at age 65. An increase in life span does not always correlate with improved health. (Image: Kennedy BK et al., Cell 159: 709-713 [2014])

Longer human life expectancy with improved treatments for fatal diseases often comes at the cost of declining quality of life and increased disability—Alzheimer's disease, dementia, frailty, vision loss, pain, joint replacement, and other conditions. Treating the underlying causes of aging may prevent this deterioration in quality of life.

Telomere length as a marker of aging

Elissa Epel of the University of California, San Francisco, discussed the relationship between stress and cell aging. Epel uses telomere length—stretches of repeat DNA at the end of chromosomes—as an indicator of aging. Chronic disease can accelerate telomere attrition; while there are myriad biochemical alterations in each disease, many diseases of aging feature the triad of oxidative stress, inflammation, and hyperglycemia / insulin resistance. For example, in diabetes the disease processes of impaired β-cell function, and resulting higher levels of biochemical stressors, further shorten telomeres.

Psychiatric diseases, particularly major depression and anxiety disorders, are also associated with shortened telomeres. Given the high comorbidity of medical and psychiatric conditions, Epel noted, it is important to consider that depression may affect aging biology, not just the physical disease condition. Treatments for diseases may further affect the rate of telomere attrition, either speeding it up or slowing it down. For example, statins and possibly metformin, used in diabetes treatment, may prevent telomere attrition, while HAART therapy in HIV may accelerate telomere attrition. Chemotherapy can work through telomere damage of cancerous as well as healthy cells. Childhood traumas followed by chronic stressors in adulthood result in shortened telomeres, which correlate with several diseases of aging, including diabetes, cardiovascular disease, stroke, and cancer. Shortened telomeres might be both a cause and a consequence of chronic disease, although this has yet to be fully confirmed.

Chairs

Ronald Kohanski

National Institutes on Aging and Geroscience Interest Group, NIH

Steven Deeks

AIDS Research Institute; University of California, San Francisco

Claudia Gravekamp

Albert Einstein College of Medicine

Arti Hurria

City of Hope National Medical Center

Jeffrey Halter

University of Michigan

Kevin High

Wake Forest University

Nir Barzilai

Albert Einstein College of Medicine

Highlights

Each person has a unique fingerprint of chronic viral infections—HIV is one example.

HIV treatment normalizes some markers of aging.

Some manifestations of diabetes are relevant to aging, others are not.

Insulin resistance in the brain may accelerate age-related cognitive impairment.

Both cancer and cancer therapies promote cellular senescence and inflammation, which contribute to aging and disease.

Cancer treatment affects areas of the brain that are also changed by aging; these treatments can promote cognitive decline.

Aging with HIV

Despite the success of antiretroviral (ARV) therapy in improving health and increasing life span, people living with HIV are at an increased risk for many age-related diseases, such as cardiovascular disease, cancer, osteoporosis, liver disease, and cognitive impairment. Several panelists stressed the need for a multidimensional approach to investigate HIV and aging, saying that researchers should consider interactions between the seven pillars of aging described during the keynote presentations and focus on possible root causes driving aging.

Although the molecular pathways of aging in people living with HIV are well understood, the field lacks high-quality biomarkers to assess the effectiveness of interventions in clinical trials. The panelists advised aging researchers to make use of the large cohorts established in HIV, particularly MACS, WIHS, and VACS. Researchers have been following both infected and uninfected subjects in these cohorts for up to 30 years, and several types of samples, including serum, DNA, plasma, and urine, are available for study.

Many factors associated with HIV infection and treatment affect pathways involved in aging. (Image courtesy of Steven Deeks)

Gretchen Neigh of Virginia Commonwealth University discussed social stress and HIV. Her work in a rhesus monkey model, used to mimic human infection, showed that previous social stress increased the viral load of simian immunodeficiency virus (SIV) and delayed ARV response. The audience was curious as to whether this effect was attributable to the virus itself or to the illness that SIV causes. This question is difficult to answer in current animal models. Neigh added that the rhesus monkey model could be useful for studying the psychosocial aspects of HIV infection and for studying how social stressors affect viral reservoirs.

Beth Jamieson of the University of California, Los Angeles, showed that ARV therapy can partially normalize DNA methylation patterns, a hallmark of aging. She would like to explore this area further to find out how factors such as duration of infection and early treatment influence this effect. One attendee suggested targeting mitochondrial dysfunction to mitigate the effects of HIV on aging. The panelists pointed to the dearth of studies linking mitochondrial dysfunction to end-organ disease and noted that several older ARVs are mitochondrial toxins, complicating such analyses. Another area of investigation is infection of macrophages by HIV. While most of the panelists focused on infection of T cells, HIV infects macrophages during later stages of disease and could be a source of persistent inflammation.

The effects of type 2 diabetes on aging

It is difficult to establish which complications of type 2 diabetes accelerate age-related effects and which are specific to hyperglycemia, unrelated to aging. For example, patients with diabetes may experience vascular complications, such as neuropathy and nephropathy. However, these effects do not occur with normal aging and are likely a specific consequence of hyperglycemia. However, as Nir Barzilai of the Albert Einstein College of Medicine reminded attendees, researchers are not starting from scratch. Metformin, a common diabetes medication, also prevents several age-related diseases. Understanding this mechanism could be a starting point from which to investigate the effect of diabetes on age-related diseases.

Several audience members asked about the role of insulin resistance in the brain. During his presentation, C. Ronald Kahn of the Joslin Diabetes Center showed that knocking out the insulin receptor in the brain increased measures of anxiety in elderly mice but not in young mice. Kahn's data also showed the importance of astroglia in insulin signaling. Attendees asked whether there were different families or subsets of astroglia in terms of insulin receptor expression or whether the cells had increased epigenetic variance with age. Kahn replied that he has not seen either effect, but added that he had not specifically looked for them.

One attendee questioned whether a homozygous knockout, which eliminates insulin signaling, is the best model for diabetes, noting that patients with diabetes retain some insulin signaling. Kahn replied that a heterozygous model may better recapitulate the biology of insulin resistance and that it may be worthwhile to use such a model.

There are many pathways and sites through which insulin resistance can affect aging in the brain. (Image courtesy of C. Ronald Kahn)

Another attendee asked about the use of CDK4 inhibitors, which are approved to treat some types of cancer. Jeffrey Halter of the University of Michigan showed that knocking out CDK4 in mice destroys β cells, which are responsible for producing insulin. Halter suggested that oncologists monitor for signs of β-cell dysfunction in patients taking CDK4 inhibitors for cancer. In addition, data from clinical trials of CDK4 inhibitors could be assessed retrospectively to evaluate whether these drugs have negative effects on β-cell function in humans.

One attendee asked the panel about the effects of asthma and decreased oxygen in obese people with diabetes and asthma. While no one on the panel has specifically investigated this relationship, the panelists cited studies in obese diabetics in which sleep apnea was shown to exacerbate insulin resistance. Improving sleep apnea decreased insulin resistance and diabetes.

Diabetes causes a subtle immunodeficiency. In other immunodeficiency models, such as HIV and transplant, cytomegalovirus (CMV) has been shown to play a role in driving vascular disease. One attendee postulated that CMV infection could be a good model to study the interaction between diabetes and aging in terms of vasculature, leukocytes, and endothelial function.

Premature aging caused by cancer and chemotherapy

Jan van Deursen of the Mayo Clinic explained that, in addition to apoptosis, chemotherapy can also induce cellular senescence in tumor cells. The panelists further explained that senescent tumor cells can be cleared by the immune system and that their ability to persist depends on the type of chemotherapy administered.

In patients with cancer, cellular senescence can occur as a consequence of normal aging or as a consequence of disease or treatment-related factors. (Image courtesy of Jan van Deursen)

Timothy Ahles of Memorial Sloan Kettering Cancer Center described how cancer and its treatment result in cognitive decline. One attendee remarked on how brain imaging in normal aging has evolved to not only monitor damage but also to look at compensatory mechanisms that may result from more serious brain damage. Ahles explained that cancer researchers have learned a lot from imaging studies of both normal aging and cognitive impairment because many of the systems affected by normal aging are also affected by cancer treatment. Wendy Demark-Wahnefried of the University of Alabama at Birmingham presented data on accelerated adverse body composition changes that occur as a result of cancer treatment, with chemotherapy inducing gains in fat and losses in muscle in the year following diagnosis that are comparable to 10 years of normal aging.

There are many good mouse models of cancer, but the disease is often studied in young animals, and studies using these models cannot investigate how aging affects cancer. The panelists noted that there has been a push in the research community to use models that develop cancers more slowly, and for researchers using models to induce cancer in older animals. However, achieving these goals can be difficult because it is time consuming and costly to maintain elderly animals. To defray some of these costs, the trans-NIH Geroscience Interest Group (GSIG) put out an RFA, joined by several other Institutes including NCI, to age animal models of disease. Funding for these research projects will be provided jointly by NIA and other relevant NIH institutes. The panelists encouraged researchers to look outside mouse models; a recent review described studies of naturally occurring cancers in pet dogs. The panelists also suggested studying cancer in nonhuman primates.

Several attendees asked about how to mitigate the effects of chemotherapy. Some patients undergo short-term fasting before chemotherapy, which has been shown to promote tumor shrinkage in mice. However, researchers have not studied whether this strategy promotes longevity, similar to the effect of dietary restriction in mice. Similarly, researchers have not systematically studied the effects of antidepressant use before chemotherapy, which has been shown to prevent negative cognitive outcomes of chemotherapy in animal models.

The panelists recommended early interventions, such as exercise during chemotherapy, to prevent or reverse decline in physical function in cancer patients. However, they also noted that later interventions can be effective. In the RENEW trial, an international sample of 641 older, long-term cancer survivors at least 5 years out from diagnosis who received materials and counseling on good dietary and exercise habits had a slower decrease in physical function than those who did not. In another initiative, cancer survivors paired with a gardener had healthier habits, improved function, and improved biomarkers of aging after one year of gardening.

Moderator

Felipe Sierra

National Institute on Aging, NIH

Highlights

There is a need for a uniform definition of accelerated aging and standardized biomarkers to monitor aging.

Researchers should identify and focus on the root causes that drive aging instead of downstream effects.

Funding agencies should ensure that suitable aging-related experiments are included in grant proposals.

A call for uniformity

The meeting ended with a panel discussion on common themes and open research questions to advance therapies for chronic diseases and aging. Several attendees mentioned the need for a uniform definition of accelerated aging. There are many ways to define aging, ranging from molecular and cellular processes to functional ability and population age. In many animal models of aging, life span is the primary outcome for aging. However, this outcome would not be informative for clinicians; it does not reveal whether a patient is experiencing accelerated or normal aging or whether a treatment is improving the effects of aging. One attendee suggested creating an NIH toolbox of biological markers of aging to provide a common vocabulary for researchers. Currently, the best biomarkers of aging are composite measures that usually include function. The panelists recommended that studies measuring aging should include data representing at least two pillars of aging, such as DNA methylation and resistance to a stressor.

Several attendees also suggested that the research community create a single database, such as those housed at WikiPathways, to organize the biological pathways involved in aging and disease. Websites that currently house this information for aging do not include information on the relationships between aging and disease.

The big picture

Several panelists noted the importance of interactions between the seven pillars of aging. However, they cautioned against focusing on any single pillar and advised that the pillars be used as a guide and not as rigid categories for aging research. It is nonetheless clear that cellular senescence and inflammation are among the most important features of aging common to the three diseases discussed at this meeting. Cellular senescence has many forms, and targeting one form may not prevent others. Several attendees pointed out that therapeutic targeting of any one marker of inflammation or cellular senescence may not remedy their underlying cause(s) and their subsequent effects on aging and disease.

Funding and resources

The panelists also noted the need for more aging studies in general. One reason that investigators are hesitant to study aging is the time and expense of using aged animal models. While some larger centers, such as the Pepper Institute at Florida State University and the Shock Center at the University of Washington, have the infrastructure to do so, smaller institutions do not. Audience members recommended that the facilities at these centers be made available to researchers, particularly junior faculty, to help recruit more people to the aging field. The panelists also noted that datasets of relevance to aging are available on the NIA website.

Another reason for the lack of aging studies is the difficulty of acquiring funding for long-term, complex studies. The panelists remarked that grant reviewers sometimes ask that aging-related experiments be removed from proposals. Instead, aging experts on review committees should ensure that such complexity is included in proposals and confirm that an appropriate model system is being used so that studies on diseases that affect the elderly are not conducted in young mice. One audience member suggested supplements to existing grants be made available to fund extra samples for aging research. For example, ancillary studies could make use of specimens collected in clinical trials to analyze predictors of aging.

General

How can we best bring together those who study disease and those who study aging?

How should clinicians define aging and accelerated aging?

What biomarkers can be used to evaluate accelerated aging in the presence of chronic diseases and to assess the effects of interventions?

What are the best animal models to study accelerated aging in the presence of chronic disease?

Are life-extending therapies that work in animal models relevant to humans, and will they also extend health?

How can funding agencies, such as the NIA, encourage investigators to consider the effects of aging in their model systems?


Effects of HIV on aging

What is the role of senescent T cells in age-related diseases?

What can epigenetic changes in T cells tell us about the link between these cells and diseases of aging?

How does psychosocial stress affect HIV pathogenesis and response to treatment in humans?

What information can be gleaned from established HIV cohorts with respect to HIV and aging?


Future research questions for HIV and aging

How do disease factors, such as duration of infection and time of treatment, influence the effects of ARV therapy on markers of aging?

What can primate models of HIV infection tell us about psychosocial aspects of disease and how social stressors affect disease reservoirs?

What role might mitochondrial dysfunction play in HIV's effect on aging?

How does infection of macrophages contribute to inflammation?


Effects of diabetes on aging

How do some diabetes therapies (eg, metformin and acarbose) increase longevity?

Which complications of diabetes are relevant to aging, and which are specific to increased blood glucose?

Could insulin resistance be a protective mechanism against accelerated aging?


Future research questions for diabetes and aging

How do CDK4 inhibitors affect β-cell function?

How do conditions that decrease the supply of oxygen, such as asthma and sleep apnea, influence insulin resistance?

What role might the immunodeficiency caused by diabetes play in driving vascular dysfunction?


Effects of cancer on aging

What are the different signs of, effects of, and treatments for cancer-related and chemotherapy-related senescence?

How can we definitively show that inflammation and coagulation affect function and survival?


Future research questions for cancer and aging

Can lifestyle changes improve cognitive function in older cancer patients?

How might short-term fasting prior to chemotherapy affect aging?

Can taking antidepressants before initiating chemotherapy mitigate cognitive decline?