EVALUATING INSTRUMENTS FOR ASSESSING HEALTHSPAN: A MULTI-CENTER CROSS-SECTIONAL STUDY IN THE COMPANION DOG

Abstract The companion dog is an emerging model in translational geroscience and offers novel opportunities to investigate aging biology and potential gerotherapeutics. However, there is a scarcity of validated tools and clinical outcome measures to characterize and understand the impact of aging in this translational species. Here we report on a multi-center, cross sectional veterinary clinical study, where we evaluated a clinical questionnaire (Canine Frailty Index; CFI; Banzato et al., 2019) to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in 451 adult companion dogs. Results support evidence of validity for the tools by confirming expectations that frailty and HRQL deteriorate with age. CFI scores were significantly higher (higher frailty) and HRQL scores significantly lower (worse HRQL) in old dogs (≥ 7 years of age) compared to young dogs (≥ 2 and < 6 years of age). Body size (small < 25lbs or large > 50lbs) was not associated with CFI or total HRQL score. However, older, larger dogs showed faster age-related decline in HRQL scores specific to owner-reported activity and comfort. Findings suggest that the clinician-assessed CFI and owner-reported VetMetrica HRQL may be useful tools to evaluate two determinants of healthspan in dogs: the accumulation of frailty and the progressive decline in quality of life. Establishing validated tools that operationalize the assessment of canine healthspan is critical for the linking pathophysiological mechanisms to aging phenotypes in the companion dog and for accelerating the development of gerotherapeutics that benefit both human and veterinary medicine.


BIOPHYTIS BIO101 IN SARCOPENIA: UPDATE ON THE SARA PROGRAM: FROM SARA-INT TOWARDS THE PHASE 3 STUDY
Cendrine Tourette, 1 Waly Dioh, 2 Carole Margalef, 2 Jean Mariani, 2 Sam Agus, 3 Rob Van Maanen, 2 and Stanislas Veillet 2 , 1. Biophytis SA, Paris, Ile- France,2. Biophytis,Paris,France,3. Biophytis Inc.,Cambridge,Massachusetts,United States Sarcopenia is a progressive muscle disorder increasing with age that may lead to mobility disability.SARA program strives to develop a viable option to treat community dwelling older adults suffering from sarcopenia.SARA-INT is a randomized three-arm interventional study (BIO101 175 mg bid / BIO101 350 mg bid / placebo) with treatment duration of 6 months.Eligibility criteria for sarcopenia were meeting FNIH criteria and Short Physical Performance Battery (SPPB) score ≤ 8/12 in men and women aged ≥ 65 years; primary endpoint was the 400-meter walking test (400MWT).233 participants aged 65 years and older were randomized, 232 and 156 participants were included in the Full Analysis Set (FAS) and Per-Protocol (PP) populations, respectively.Due to COVID-19 pandemic, most end-of-treatment efficacy assessments are missing for 55% of the participants, reducing the studies' power.BIO101 350 mg bid treatment led to an improvement in the primary endpoint, the gait speed from the 400MWT of 0.07 m/s in the FAS population (not statistically significant) and of 0.09 m/s in the PP population (nominally statistically significant, p=0.008) after 6 months; this is close to MCID in sarcopenia (0.1 m/s).BIO101 350mg bid treatment effect on the 400MWT is confirmed in PP sub-populations at high risk of mobility disability.Trends were observed with other endpoints.BIO101 showed a very good safety profile at both doses.Biophytis will initiate the phase 3 program by end 2022, targeting a severe sarcopenic population.Outcomes of the interactions with regulatory agencies on study design will be presented.

PATTERNS OF MULTIMORBIDITY IN AGING, RADIATION-EXPOSED NON-HUMAN PRIMATES
Ellen Quillen, 1 Maggie Stainback, 1 Jamie Justice, 2 John Olson, 1 George Schaaf, 1 and J. Mark Cline 1 , 1. Wake Forest School of Medicine,Winston Salem,North Carolina,United States,2. Wake Forest School of Medicine,North Carolina,United States Resilience to stressors is a major component of biological aging and may mediate the onset of multimorbidity in older adults.The Wake Forest Non-Human Primate Radiation Survivor Cohort (RSC) provides a novel opportunity to study aging and resilience in 250 rhesus macaques (Macaca mulatta) with single-dose radiation exposures 0-15 years prior and 50 controls with semi-annual clinical, imaging, and biomarker measurements taken over their lifespan.Multimorbidity is extremely common among irradiated animals.Only 38% of animals have none of 20 common chronic diseases, falling to 16% of animals over age 8 and 11% over age 10 (middleaged animals).70% of animals have 5 or more diagnoses in this oldest cohort.The presence of any one disease increases the likelihood of having a second, co-morbid condition.Nevertheless, some animals continue disease-free until late in life, highlighting substantial variability in resilience.To identify patterns of multimorbidity, survival curves for each diagnosis were generated for age and time since radiation and k-median clustered resulting in four groupings of aging-associated morbidities.Bone, brain, and gastrointestinal disorders arise 3.5 years after radiation on average, followed by skin, heart, and cataracts.At 4.65 years, animals are at increased risk of being underweight and overweight and developing diabetes, hypertension, and hepatic dysfunction.Tumor, lung, and kidney disorders arise approximately 6 years after exposure.In all cases, these age-related disorders occur significantly earlier in irradiated animals than controls.These findings highlight the clustering of multimorbidities in aging, radiation-challenged primates and the potential of the RSC in studying resilience.

EVALUATING INSTRUMENTS FOR ASSESSING HEALTHSPAN: A MULTI-CENTER CROSS-SECTIONAL STUDY IN THE COMPANION DOG
Frances Chen, 1 Tarini Ullal, 2 Jessica Graves, 3 Ellen Ratcliff, 3 Alexander Naka, 3 Brennen McKenzie, 3 Tennery Carttar, 3 and Michael LaCroix-Fralish 4 , 1. Loyal, part of Cellular Longevity Inc, San Francisco, California, United States, 2. University of CA,Davis,Davis,California,United States,3. Cellular Longevity Inc,San Francisco,California,United States,4. Marist College,Poughkeepsie,New York,United States The companion dog is an emerging model in translational geroscience and offers novel opportunities to investigate aging biology and potential gerotherapeutics.However, there is a scarcity of validated tools and clinical outcome measures to characterize and understand the impact of aging in this translational species.Here we report on a multi-center, cross sectional veterinary clinical study, where we evaluated a clinical questionnaire (Canine Frailty Index;CFI;Banzato et al., 2019) to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in 451 adult companion dogs.Results support evidence of validity for the tools by confirming expectations that frailty and HRQL deteriorate with age.CFI scores were significantly higher (higher frailty) and HRQL scores significantly lower (worse HRQL) in old dogs (≥ 7 years of age) compared to young dogs (≥ 2 and < 6 years of age).Body size (small < 25lbs or large > 50lbs) was not associated with CFI or total HRQL score.However, older, larger dogs showed faster age-related decline in HRQL scores specific to owner-reported activity and comfort.Findings suggest that the clinician-assessed CFI and owner-reported VetMetrica HRQL may be useful tools to evaluate two determinants of healthspan in dogs: the accumulation of frailty and the progressive decline in quality of life.Establishing validated tools that operationalize the assessment of canine healthspan is critical for the linking pathophysiological mechanisms to aging phenotypes in the companion dog and for accelerating the development of gerotherapeutics that benefit both human and veterinary medicine.

SEX DIFFERENCES IN LIFESPAN RESPONDING TO EARLY AND LATE ONSET DIETARY RESTRICTION
Nisi Jiang, Vivian Diaz, Randy Strong, and James Nelson, UT Health San Antonio, San Antonio, Texas, United States Dietary restriction (DR) extends lifespan in many animal models.In mice, a range of factors affects the magnitude of the pro-longevity effect of DR, including the strain, restriction level, sex, and age of treatment onset.Early onset DR dramatically prolongs lifespan, whereas DR started later in life has diminished or no significant effect.The lifespan responses of males and females to DR also differ.Whether there is a sex difference in the lifespan response to the age of onset of DR has not been examined.Probing the basis for the variable response to DR can help elucidate the underlying mechanisms that mediate lifespan extension.We diet restricted UM-HET3 mice of both sexes from either 5 months (early-onset) or 20 months (lateonset) of age and monitored their survival.Early onset DR significantly prolonged lifespan in both males and females, which increased median lifespans by 54% and 18.5%, respectively.By contrast, although late onset DR prolonged lifespans in both sexes, the magnitude of increase in males (1.4%) was significantly lower than in females (15.8%, p=0.0474).Moreover, the decrease in the magnitude of the response to late-onset DR compared to that of earlyonset DR is more dramatic in males than females.Further analysis found a significant interaction (p=0.0001) between early and late-onset DR in males but not in females (p=0.3818).Together, these results indicate that the lifespan response to delayed onset of DR diminishes more in males than in females, providing another model to probe the underlying mechanisms of DR.

FOOD AND SUPPLEMENT COMBINATIONS TO PREVENT OR POSTPONE AGING, MCI, AND ALZHEIMER'S DISEASE.
Alec Pruchnicki, 1 Barrie Kavasch, 2 Barrie Sachs, 3 Roseanne Schnoll, 4 and Rolf Martin 3 , 1. Vista on 5th, New York,New York,United States,2. Blueberry Study MMT Corporation,Sherman,Connecticut,United States,3. MMT Corporation,Sherman,Connecticut,United States,4. Brooklyn College,CUNY,Sherman,Connecticut,United States Evidence of many interacting causes of aging has renewed interest in food and nutrient combinations that may blunt the main causes[PMC9184560, PMC8889622] and postpone aging, mild cognitive impairment and Alzheimer's ("A-MCI-Alz") in contrast to prior failures [PMC9232186].We present an updated list of anti-aging/pro-longevity strategies to address limitations of previous food/nutrient combinations.The four levels of aging include the specific disease, the systemic complications that lead to the disease, the loss of cellular integrity that affects the system, and macromolecule malfunction that alters cellular integrity.Similarly, Our list has two unusual features: (i) all interventions should be administered concurrently so no fundamental causes of A-MCI-Alz are without remediation and can inflame and leave smoldering important causal factors, (ii) all interventions should be provided daily or weekly to help avoid re-ignition of key factors driving A-MCI-Alz.These two features can help explain past longevity-trial failures[PMC9310407]: no previous study to our knowledge has included most or all of the following interventions, so untreated causes of A-MCI-Alz likely remained active[PMC9114803].