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Geroscience – Drugs to Retard Aging

Drugs to retard aging, , , , , ,

Introduction

Geroscience is the rapidly expanding field of gerontology with a specific objective beyond that of understanding aging.  Instead, it is evaluating drugs to retard aging. Specifically, it states that the goals of aging research are “best achieved by novel integrated approaches to health and disease with the understanding that biological systems change with age” (Kennedy et al., 2014).  Since aging is the major risk factor for disease, geroscience recommends that rather than treat age-related diseases one by one, physicians should instead “treat” aging.  Hence, the focus should be to identify future drugs to retard aging.  If age changes are delayed, prevented or reversed, diseases would likewise be delayed.  Therefore, drugs to retard aging would lengthen the healthspan and provide years lived with good health and not in management of disease.

Geroscience proposes the Unified Hypothesis of Aging.  This hypothesis states that all age changes are interrelated.  Thus, according to this hypothesis, pharmacological reduction i.e. drug-dependent reduction of one aspect of aging will decrease the other aspects of aging.  A trans-National Institutes of Health Geroscience Interest Group Summit (2019) established a consensus on age changes.  Age changes are Pillars of Aging or Hallmarks of Aging.  

Hallmarks of Aging

Prominent age changes investigated over the years are identified as follows (Lopez-Otin et al., 2013): 

1.  Loss of genetic stability

Damage to both nuclear and mitochondrial DNA accumulates over the years resulting in a variety of changes (mutations, deletions) that reduces the ability of the DNA to do its job i.e. direct production of proteins.  This loss leads to abnormal cell function and future tissue/organ incompetence.

2.  Reduction in telomere length

This is a popular topic.  Several companies offer services to measure telomere length implying that telomere length is a surrogate of  biological age, that is the longer the telomeres, the younger the individual.  Telomeres are the protein-nucleic acid complexes at the ends of each chromosome.  Telomeres function to prevent the ends from “sticking” together during DNA replication in cell division. With each replication, the length of the telomeres shorten until they are too short to provide protection.  This stops future cell division and prevents the biological advantage of cell renewal.  No new cells are formed.

3.  Epigenetic alterations

These are changes in the expression of DNA.  The structure of DNA i.e. the genetic code is not altered.  In contrast, epigenetic alterations influence which genes are expressed (turned on to make proteins and which are turned off and make no protein).  Epigenetic alterations turn on genes that produce inflammatory proteins and turn off genes that make anti-inflammatory proteins, fostering a state of age-dependent chronic low grade inflammation.    

4.   Loss of protein stability

Proteins require correct folding and appropriate disposal when no longer needed.  The complex systems regulating these activities deteriorate with age.  The result is accumulation of toxic incompetent proteins

5.  Altered nutrient sensing

Nutrient sensing complexes detect high glucose, amino acids and levels of energy.  The most famous nutrient sensor is insulin and its relative, insulin growth factor (IGF).  Moderation and/or suppression of these sensors in animal models of aging increases the healthspan and lifespan.

6.   Mitochondrial dysfunction

Mitochondria are subcomponents (organelles) of the cell and are responsible for generating the main energy molecule, ATP.  Another key function of mitochondria is the ability to generate the signals to terminate the life of a cell in the presence of irreparable damage.  As mitochondria become dysfunctional with age, less energy is generated and cells disappear.

7.   Cell senescence

This hallmark has been previously discussed (see Blog 23).  Cells that experience unusual stress e.g. excessive DNA damage, high levels of growth factors, repetitive cell division, mitochondrial dysfunction may become senescent.  Senescent cells enlarge, are hypermetabolic producing unwanted negative factors and resist cell death by inhibiting all mechanisms for cell suicide.  They accumulate with age and accelerate aging.  

8.   Stem cell exhaustion

At younger ages, damaged cells generally disappear by programmed cell suicide. Stem cells, pluripotent cells that become any cell type given the correct niche and support factors, come to the rescue.   With age, stem cell number and functionality decline. Lost cells are not replaced and tissues and organs must function with reduced cell numbers.

9.  Abnormal intercellular communication

Communication among cells is facilitated in large part by circulating factors such as hormones and small molecules secreted by immune cells.  Both of these sources diminish with age.  This weakens communication between cells and disrupts organ function.

Drugs to Retard Aging

There is a flourishing number of compounds with potential to inhibit the hallmarks of aging and extend the healthspan in humans.  The majority of these compounds are repurposed drugs.  They include metformin (antidiabetic), rapamycin (immunosuppressant), anticancer drugs quercetin, dasatinib, and fisetin and resveratrol (OTC supplement).  Treatment of animal models of aging (roundworm, flies, mice) with these drugs has produced spectacular results.  These are 1)  rejuvenation of aged organs, 2) reversal of decline in exercise capacity and cardiopulmonary, and metabolic function, 3) delayed onset of disease, and 4) significant extension of maximal lifespan. 

These drugs are now under investigation in man.  Several pilot studies and phase 1 clinical trials have been completed and many more are in the early stage of recruitment.

Resveratrol

Probably the most famous anti-aging drug is resveratrol, a naturally occurring compound extracted from Veratrum grandiflorum (flowering herb), grapes, wine, and soy.  In clinical trials ranging from a few days to months (doses 5 -5000 mg), obese participants experienced consistent reduction in body weight, and lowering of systolic blood pressure and blood sugar.  Several more potent analogues of resveratrol have undergone clinical testing with modest anti-inflammatory and lipid lowering effects.  To date,  the variable pharmacokinetics of resveratrol analogues hindered the expected efficacy seen in animal studies.

Dasatinib and Quercetin

In contrast to the very modest effects of resveratrol analogues, dasatinib (D) and quercetin (Q) (given together intermittently, 3 days for 3 weeks).improved physical function of walking distance, gait speed and chair-stands in 14 elderly patients with pulmonary fibrosis.  A second pilot study administered D+Q for 3 days to 9 patients with diabetic kidney disease. Eleven days post treatment there was a reduction in senescent cells in tissue biopsies of fat, skin and blood.  Undesirable factors known to be secreted by senescent cells were also reduced.  Additional trials are in progress to test the efficacy of D+Q and related drugs in chronic kidney disease, Alzheimer’s Disease, osteoarthritis, and frailty.

Rapamycin

As of April 2023, there are 7 clinical trials evaluating rapamycin as an inhibitor of hallmarks of aging.  These are small placebo controlled trials (34-150 participants, age 60-95).  Additionally, eight other trials with rapamycin treatment assessing immune, cognitive and cardiac function and/or physical responses have been completed but with no publications as yet. 

Metformin

Finally, the inspirational drug for the search for anti-aging drugs is metformin.  In 2013, the FDA for the first time ever, approved a clinical trial to retard aging.  Clinicians will treat 3000 subjects for 6 years with a daily dose of metformin or a  placebo with the  goal of delaying the onset of age-related diseases (https://www.afar.org tame trial).  Metformin treatment of animal models of aging reduced several hallmarks of aging and increased the lifespan.  Observational studies reported that older adults taking metformin for diabetes lived longer than their non diabetic counterparts not taking metformin.  Additionally, metformin offers several advantages: it is inexpensive, has few to no side effects, and has been on the market for more than 20 years with an excellent safety record.  Sadly this study has yet to start due to lack of public funding.

Critique and Considerations

Although there are numerous small pilot studies in the works as well as many completed studies, this is really only the beginning, albeit a remarkable endeavor.  In general, the success of some pilot studies suggests that the hypothesis of retarding the hallmarks of aging is worth pursuing.  However, these initial studies are of short duration and provide no information on long term adverse or toxic effects.  Therefore, larger and longer studies are essential but as with the metformin trial, serious financial support will be difficult to find.   Even clinical success of a repurposed drug offers little monetary reward for a multimillion dollar investment in a large long term clinical trial.  

Select References

Chaib S  Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 28(8): 1556–1568, 2022.

Dai H, Sinclair DA, Ellis JL, Steegborn C. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol Ther. 188: 140–154, 2018.

Justice JN et al. Development of Clinical Trials to Extend Healthy Lifespan. Cardiovasc Endocrinol Metab 7:80–3, 2018.

Kennedy BK. et al., Aging: a common driver of chronic diseases and a target for novel interventions. Cell 159(4): 709–713, 2014. 

Kulkarni AS, et al. Metformin Regulates Metabolic and Non metabolic Pathways in Skeletal Muscle and Subcutaneous Adipose Tissues of Older Adults.  Aging Cell 17(2):e12723, 2018.

Lopez-Otin et al., The Hallmarks of Aging. 153(6): 1194–12171, 2013.

Luis C et al., Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging – from theory to practice. Front. Nutr. 9:958563, 2022.

Walters HE, Cox LS.  mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases. Int. J. Mol. Sci.19: 2325, 2018.

Wissler EO et al., Strategies for Late Phase Preclinical and Early Clinical Trials of Senolytics. Mech Ageing Dev. 200: 111591, 2021

Insight 9 – Replacement for caloric restriction

Diet, Individual controls aging, , , , ,

The caloric restriction mimetic – better than starvation

Caloric restriction (CR) is severe reduction in calorie intake.  It must be maintained for an extended period of time and be supplemented with essential nutrients.  It is often called “starvation without malnutrition”.  However, the reward of this difficult protocol is exceptional:  a longer and healthier lifespan (see Insight 8).  The obvious problem is that, unlike animals under investigative experimentation, humans cannot endure this degree of starvation for any significant length of time.  Thus the search for drugs that would produce the same benefits of CR without the pain of eating less.  These drugs are termed caloric restriction mimetics (CRMs).

The caloric restriction mimetic – 3 of interest:

1.  Sirtuin (SIRT)-activating compounds e.g. resveratrol

2.  Metformin

3.  Rapamycin

Sirtuin-activating compounds

Sirtuin-activating compounds stimulate specific genes (SIRTs) to produce proteins termed sirtuins.  Sirtuins (chemically defined as NAD histone deacylases), in turn, act to change cell metabolism for the better.  Sirtuins perform several significant functions.  Some of these are 1) reduction of inflammation through depression of the master gene (NF-κβ), 2) greater recycling of damaged proteins, and  3) improvement of insulin signaling.  Together these activities and many more contribute to a healthier life.

How are sirtuins related to CR?  In animal models of aging, CR activates the genes (SIRT family) that produce the sirtuins and consequently, the level  of sirtuins increases with CR.  Secondly, in genetic experiments which insert an extra SIRT gene into an experimental animal, the level of sirtuins increases and beneficial changes comparable to CR occur.  So chemicals that elevate the level of sirtuins should produce the same beneficial effects of CR.  Thus the development of sirtuin-activating compounds.

Resveratrol – role in caloric restriction

A notable sirtuin-activating compound is resveratrol, originally isolated  from red wine and when concentrated (1000 fold), resveratrol produces effects similar to CR such as an increase in maximal lifespan, reduced inflammation, and delay in disease onset.   Unfortunately, resveratrol is poorly absorbed by the gastrointestinal tract and so analogs with greater bioavailability have been developed.  Analogues have been evaluated in rodents and in man.  Generally in rodents, improved health benefits e.g. delay in disease onset have been observed. 

In man, clinical trials assessing one particular analogue, SRT2104, for therapy of psoriasis, ulcerative colitis, sepsis, and vascular dysfunction in smokers and type 2 diabetes (T2D) have been completed.  Thus far only results for the effect of oral SRT2104 on psoriasis have been published and showed reasonable safety and a modest reduction of disease pathology.  This was a small study (40 patients, 84 days of treatment) that warrants additional evaluation according to Kreuger et al., (2015).   As published results become available, updates will be provided.

Metformin

Metformin is a caloric restriction mimetic.  It is also an FDA approved drug for treatment of T2D. Much is known on how it works to block production of glucose by the liver.  A striking finding was that patients taking metformin for T2D lived longer than those without diabetes and of course not taking metformin.

When used in animals, metformin delays the onset of disease and in some animal models of aging, it extends the lifespan.   It acts in multiple ways to alter nutrient sensing and improve cellular activities related to gene function, recycling of damaged cell components and slowing age-related changes.  These changes mirror those produced by lifelong CR. 

To further understand the caloric restriction mimetic effects of metformin, the FDA (2016) granted approval of its use in a clinical trial to determine whether metformin will delay the onset of disease.  The trial named Targeting Aging with Metformin (TAME) trial will enroll 3000 patients (65-79 years of age) and follow them for 6 years to determine whether metformin delays the onset of major age-related diseases e.g. heart disease, cancer and dementia (https://www.afar.org/tame-trial).  The results are eagerly awaited.

Rapamycin

Rapamycin is an antibiotic and potent immunosuppressant drug to prevent organ rejection.  In animal models of aging including the mouse, treatment with rapamycin extends the lifespan and delays the onset of age-related diseases.  Thus rapamycin is a caloric restriction mimetic.  It acts by inhibiting an important nutrient sensor called mTOR.  This nutrient sensor is activated by insulin.  Therefore, in the presence of rapamycin,  insulin-mediated metabolic effects are significantly reduced. 

Chronic use of rapamycin in man is limited to very low doses due to untoward side effects. However, the Dog Aging Project completed a placebo-controlled trial with 24 healthy companion dogs treated with a low dose of rapamycin for 10 weeks.  The drug is safe and improves cardiac function as determined by an echocardiogram before and after treatment.  Funded by a grant from National Institute of Aging and private donors, the next experiment will enroll a larger number of companion dogs and seek to determine whether aging can be delayed in dogs with this CRM.  

The objective of the Dog Aging Project (dogagingproject.org) is to understand aging in dogs and translate the information to humans.  This is based on observations that humans and dogs share the same environment, they have many biological mechanisms in common and also develop many of the same diseases.  Insights into dog aging should contribute to understanding human aging.

Comparison of diet and mimetics

Common Pathway

The schematic illustrates one known pathway altered by CRMs.  As with CR, these drugs also target the nutrient sensor termed mTOR (mammalian target of rapamycin).  This sensor was uncovered in part with studies using rapamycin.  mTOR is a key protein that affects many other essential pathways in the cell.  When its activity is reduced, more efficient metabolism ensues, recycling is enhanced and inflammation is minimized. The future caloric restriction mimetic will potentially replace dietary caloric restriction.

References of interest

1.  Krueger JG, Suarez-Farinas M, Cueto I et al.  A randomized, placebo-controlled study of SRT2104, s SIRT1 activator in patients with moderate to severe psoriasis. PLoS ONE 10(11): e0142081

2.  Kulkarni AS, Gubbi S, Barzilai N.  Benefits of metformin in attenuating the hallmarks of aging.  Cell Metab 32:  15-30, 2020.

3.  Urfer SR, Kaeberlein TL, Mailheau S.  A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle aged companion dogs.  GeroScience 39:117–127, 2017.